REVIEWS

The cell biology of mitochondrial

membrane dynamics
Marta Giacomello1, Aswin Pyakurel1,2, Christina Glytsou1,2 and Luca Scorrano   1,2 ✉
Abstract | Owing to their ability to efficiently generate ATP required to sustain normal cell function,
mitochondria are often considered the ‘powerhouses of the cell’. However, our understanding of
the role of mitochondria in cell biology recently expanded when we recognized that they are key
platforms for a plethora of cell signalling cascades. This functional versatility is tightly coupled
to constant reshaping of the cellular mitochondrial network in a series of processes, collectively
referred to as mitochondrial membrane dynamics and involving organelle fusion and fission
(division) as well as ultrastructural remodelling of the membrane. Accordingly , mitochondrial
dynamics influence and often orchestrate not only metabolism but also complex cell signalling
events, such as those involved in regulating cell pluripotency , division, differentiation, senescence
and death. Reciprocally , mitochondrial membrane dynamics are extensively regulated by post-
translational modifications of its machinery and by the formation of membrane contact sites
between mitochondria and other organelles, both of which have the capacity to integrate inputs
from various pathways. Here, we discuss mitochondrial membrane dynamics and their regulation
and describe how bioenergetics and cellular signalling are linked to these dynamic changes of
mitochondrial morphology.

Krebs cycle
A series of chemical reactions
catalysed by enzymes that,
on oxidation of the acetyl
portion of acetyl coenzyme A,
generate reducing equivalents
(NADH and FADH2).
Membrane contact sites
Points at which two biological
membranes run in parallel, at a
constant distance, for several
nanometres.
1
Department of Biology,
University of Padua,
Padua, Italy.
2
Veneto Institute of Molecular
Medicine, Padua, Italy.
✉e-mail: luca.scorrano@
unipd.it
https://doi.org/10.1038/
s41580-020-0210-7
After the discovery of the Krebs cycle in the 1950s,
mitochondria were primarily associated with cellular
bioenergetics. This view changed in the 1990s when
mitochondria were shown to be important contribu-
tors to apoptotic cell death1. These discoveries paved
the way to the idea that these organelles have a role in
cell signalling, as now corroborated by ample evidence.
Accordingly, mitochondria have been implicated in
several complex cellular processes beyond cell death2,3,
ranging from autophagy4,5 to stem cell differentiation6,7
and regulation of immune response8 (Fig. 1a).
The twofold role of mitochondria as cellular pow-
erhouses and signalling organelles is paralleled by the
fact that they are surrounded by two membranes: an
inner mitochondrial membrane (IMM) and an outer
mitochondrial membrane (OMM), characterized by
different composition and function (Fig. 1b). The IMM
delimits the mitochondrial lumen (matrix) and can be
further divided into two subcompartments: the inner
boundary membrane, running parallel to the OMM, and
the cristae — deeply convoluted, pleomorphic invagi-
nations that provide the expansion of the surface area
and harbour the machinery required for mitochondrial
respiration (Fig. 1b). By contrast, the OMM is smooth
and generally permeable (it only limits diffusion of mol-
ecules bigger than ~5,000 Da) and behaves as a platform
where cell signalling pathways converge, are decoded
and are transmitted into mitochondria. Moreover, the
OMM forms interfaces with other subcellular compart-
ments — including prominently the endoplasmic reticu-
lum (ER), but also lysosomes, peroxisomes, endosomes,
melanosomes, lipid droplets and the plasma membrane
— to establish membrane contact sites (Fig. 1c).
The multifaceted involvement of mitochondria in cell
biology is accompanied by their high degree of morpho-
logical variability. Since early in mitochondrial research,
it has been well established that mitochondria can come
in different shapes, with both their overall (length,
width, roundness) and their ultrastructural (organi-
zation of the mitochondrial membranes) morphology
showing large variation between cells, during cell cycle
and on metabolic or cellular signals. The name of these
organelles, which was coined by Carl Benda in 1898,
is the combination of the Greek words for ‘thread’ and
‘grain’9. Indeed, mitochondria can be found as isolated
organelles or joined to form larger networks; they can
also be distributed unevenly (through regulated mito-
chondrial transport and positioning) in the cytosol to
match local energy demands of the cell10. This changea-
ble and adaptable nature of mitochondria involving their
morphology and subcellular distribution is collectively
known as mitochondrial dynamics. Here, we focus spe-
cifically on mitochondrial membrane dynamics and
remodelling of mitochondrial morphology; for a review

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a b
Autophagy Crista Crista IMM (IBM) ATP K+
Cell death junction channel MCU
Inflammation and Differentiation OMM IMS ATP
senescence synthase
Mitochondrion
K+
OPA1
Metabolism Stem cell Respiratory
maintenance chain Ca2+
Innate immune Migration complexes
response
Mitofusin Metabolites/
Matrix IMS proteins

c Plasma membrane
Melanosome
ER
Solute carriers/
MICOS Cytochrome c channels,
metabolite
exchangers
Lysosome

Mitochondrion d Basal condition

Fission Fusion

Lipid
droplet IMS MDC
Endosome protein
Peroxisome MDVs

Misfolded • Clearance of damaged • Increased ATP production

Lysosome mitochondrial mitochondria (mitophagy) • Exchange of matrix
Peroxisome membrane • ROS production content
protein • Mitochondrial distribution

Fig. 1 | Mitochondrial structure and function. a | Mitochondria coordinate
various cellular functions. Key processes dependent on mitochondria are
listed. b | Mitochondrial structure. The mitochondrial lumen (named ‘matrix’,
which is the site of the Krebs cycle, mitochondrial DNA replication, protein
biosynthesis) is surrounded by two membranes: the outer mitochondrial
membrane (OMM) and the inner mitochondrial membrane (IMM). The OMM
acts as a diffusion barrier and also mediates the transduction of signals into
and out of mitochondria. The IMM includes two main subcompartments:
the inner boundary membrane (IBM) and mitochondrial cristae. The IBM
runs parallel to the OMM and hosts various channel transporters that
shuttle ions, ATP, ADP and small metabolites between the cytoplasm and the
matrix. Mitochondrial cristae are membrane invaginations that serve as sites
for oxidative phosphorylation (harbouring respiratory chain complexes and
ATP synthase), mitochondrial DNA maintenance and iron–sulphur cluster
biogenesis. Cristae are connected to the IBM via cristae junctions, which are
narrow clefts that close the cristae and thereby prevent the contents of the
cristae from being released into the intermembrane space (IMS). Shaping
the IMM into cristae depends on various membrane-shaping proteins,
including the mitochondrial contact site and cristae organizing system
(MICOS), which localizes to cristae junctions and also establishes contacts
between the IMM and the OMM by interacting with outer membrane
protein complexes, dynamin-related protein optic atrophy protein 1 (OPA1),
which forms oligomers at cristae junctions, disruption of which is associated
with cristae opening and ATP synthase dimers, which were shown to
oligomerize into long double rows running along the cristae ridges.
c | The OMM establishes networks of interactions with other organelles,
including membrane contact sites with the endoplasmic reticulum (ER),
plasma membrane, lysosomes and endosomes, lipid droplets, peroxisomes
and melanosomes. These membrane contacts sites regulate mitochondrial
functions. In addition, mitochondria release mitochondrial-derived vesicles
(MDVs) and mitochondrial-derived compartments (MDCs), which
incorporate mitochondrial components. MDVs can communicate with
other organelles (lysosomes and peroxisomes), while MDCs are important
for mitochondrial quality control by removing misfolded proteins from
mitochondrial membranes (Box 3). d | Mitochondrial shape is fundamental
for mitochondrial (metabolic) activity. For example, the efficiency of ATP
production is increased and the exchange of matrix content is favoured in
fused organelles. By contrast, fragmented organelles produce more reactive
oxygen species (ROS) and are efficiently cleared by mitophagy. However,
mitochondrial fragmentation is also required for the equivalent distribution
of mitochondria to daughter cells on cell division. MCU, mitochondrial
Ca2+ uniporter.

of mitochondrial transport and subcellular distribution,
the reader is referred to ref.11.
The two main mechanisms of mitochondrial mem-
brane dynamics are fusion and fission (division).
Another important aspect of mitochondrial membrane
dynamics encompasses biogenesis and remodelling of
mitochondrial cristae. The experimental observations
that mitochondrial appearance changes depending on
the cellular context have at least two far-reaching implica-
tions. First, they suggest that mitochondrial morphology/
shape (these two terms are used interchangeably to
refer to the visual characteristics of these organelles)
can be dynamically modulated, not only by the struc-
tural components (that is, the lipids and proteins that
determine the structure of mitochondrial membranes)
but also by signalling pathways. Second, they also

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Table 1 | Human diseases caused by mutated fission/fusion factors Inner mitochondrial membrane. The cristae of the
IMM are the principal site of oxidative phosphorylation
gene Disease refs (OXPHOS), since they host all the complexes implicated
DRP1 Encephalopathy 264
in mitochondrial respiration, including the mitochondrial
Autosomal dominant optic atrophy 265 respiratory chain and the F1Fo-ATP synthase13,14. Furthermore,
cytochrome c, the only soluble OXPHOS member, local-
Microcephaly and pain insensitivity 266
izes mainly in the intracristal compartment3,15. Hence, the
GDAP1 Charcot–Marie–Tooth disease, axonal, type 2K , recessive 267
primary function of the IMM is bioenergetics, whereby
intermediate A , type 4A
the free energy stored in the reducing equivalents produced
INF2 Charcot–Marie–Tooth disease, dominant intermediate E 268
in the Krebs cycle is converted into ATP (Supplementary
Glomerulosclerosis, focal segmental, 5 269 Box 1). In addition, the ‘neck’ of cristae, called a cristae
MFF Leigh-like encephalopathy , optic atrophy and peripheral neuropathy 270 junction, can confine metabolites, proteins (such as
cytochrome c but also others) and solutes within the
Encephalopathy due to defective mitochondrial and peroxisomal 271

fission
MFN2 Charcot–Marie–Tooth disease type 2A , hereditary motor and sensory
neuropathy VIA
OPA1 Optic atrophy 1
Behr syndrome
Mitochondrial DNA depletion syndrome
Syndromic Parkinson disease and dementia
Oxidative phosphorylation
(OXPHOS). A process involving
coupling between mitochondrial
respiration and ATP production.
Mitochondrial respiratory
chain
An ensemble of protein
complexes whose coordinated
activity catalyses the oxidation
of reducing equivalents using
oxygen as a terminal electron
acceptor.
F1Fo-ATP synthase
Protein complex located at the
inner mitochondrial membrane
which mediates Pi addition
to ADP to generate ATP in a
process driven by the passage
of protons.
Reducing equivalents
Electron donors in a redox
reaction, which become
oxidized. In mitochondria,
NADH and FADH2.
64
66,67
272
273
274
suggest that mitochondrial morphology participates in
mitochondrial adaptation to specific cellular and tissue
demands, and governs mitochondrial response to cyto-
solic signals: for example, mitochondrial morphological
changes are not only the consequence of the recruitment
of mitochondria in the cell death pathways but occur,
for example, in response to nutrient stress, when mito-
chondria first elongate and then fragment12 (Fig. 1d).
It is thus not surprising that deregulation of mitochon-
drial dynamics (and in particular of fusion and fission)
has been linked to several genetic disorders in humans
(Table 1) and that the molecular effectors of these pro-
cesses are subject to various post-translational mod-
ifications (PTMs; Table 2), which allow the coupling
of mitochondrial membrane dynamics to cell signal-
ling, reflecting the sensitivity and responsiveness of
mitochondrial dynamics to cellular states.
In this Review, we discuss the key mechanisms of
mitochondrial membrane dynamics, focusing on our
progress in understanding how these dynamics link
to cell function. We specifically highlight the interplay
between mitochondrial membrane dynamics and cell
signalling as well as the connectivity of mitochondria
to other organelles via membrane contact sites. At the
end of this Review, we hope that the reader will under-
stand that mitochondrial morphology is influenced by
the effect of cellular signals impinging on mitochondrial
dynamics and by the close connection between mito-
chondria and other organelles, and reciprocally that
mitochondrial morphology influences not only mito-
chondrial bioenergetics but also the metabolic pathways
and signalling cascades converging on mitochondria.
Mitochondrial membranes
Mitochondria are surrounded by two structurally and
functionally different membranes. While the IMM is
mostly implicated in mitochondrial energy conversion,
the OMM is the principal platform for mitochondrial
signalling.
cristae lumen (Fig. 1b).
We identify two main functional consequences of the
extreme compartmentalization of the IMM. The first
impacts on bioenergetics. Cristae organization ensures
the optimal conditions for ATP production, minimiz-
ing the diffusion of metabolites, protons and ADP
during respiration16. Super-resolution imaging offers
a formal proof to this concept, identifying individual
cristae with different magnitudes of transmembrane
potential17. Accordingly, on activation of mitochondrial
respiration, cristae tighten, a process that can enhance
overall OXPHOS efficiency18–21. The second functional
consequence impacts on apoptosis. Because during
apoptosis cytochrome c is required in the cytosol for
the activation of effector caspases3, it must be released
from mitochondria. During cell death, cristae there-
fore undergo a process of dramatic structural changes,
referred to as ‘cristae remodelling’, that supports the
intramitochondrial redistribution of cytochrome c from
the cristae to the intermembrane space, followed by its
complete release to the cytosol through apoptotic pores
in the OMM. Therefore, IMM organization into cristae
needs to be tightly controlled. Mechanisms involved in
regulating cristae organization will be discussed in the
following section.
Outer mitochondrial membrane. Originally the barrier
between the invading endosymbiont and the hostile
cytosol environment of the host cell, the OMM evolved
into a platform for signalling events that use mitochon-
dria. The OMM hosts proteins that are fundamental for
the organelle (and hence cell) physiology. They include
translocases mediating the transport of mitochondrial
precursor proteins; proteins that physically connect
mitochondria with other subcellular compartments in
specific sites known as membrane contact sites; and
proteins that coordinate signal transduction pathways
with mitochondrial function. Finally, the OMM is cru-
cial for mitochondrial dynamics because it hosts all the
molecules involved in mitochondrial fusion and fission
(see later).
The list of signalling cascades that use the OMM as
a platform grew to the point that mitochondria are now
considered ‘signalling organelles’, and this list is exten-
sively covered by dedicated reviews22,23. For the scope
of this Review, it is interesting to note that in several
circumstances these signalling cascades are controlled
by, or influence, mitochondrial dynamics. To give the
reader a sense of the extent of this reciprocal influence,

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Table 2 | Key post-translational modifications of mitochondrial dynamics proteins

Protein Modification Biological effect refs
DRP1 Phosphorylation (Ser585 and Ser616) by Promotes mitochondrial fission in mitotic cells 198

CDK1–cyclin B
Phosphorylation (Ser637) by PKA Inhibits fission by reducing DRP1 GTPase activity 104

Phosphorylation (Ser 600) by CaMKIα Activates fission 198

Dephosphorylation by calcineurin Activates fission 105

Sumoylation (Lys532, Lys535, Lys558, Lys568, Positively regulates mitochondrial fission 139,275

Lys594, Lys606, Lys608) by MAPL

S-Nitrosylation (Cys644) Increases DRP1 dimerization and mitochondrial 145

fission; causes neuronal damage

Ubiquitylation by APC/C components Targets DRP1 for proteasomal degradation, allowing 204

mitochondrial elongation after release from mitotic

arrest
Ubiquitylation by MARCH5 Targets DRP1 for proteasomal degradation; 276

decreases mitochondrial fission

FIS1 Ubiquitylation by MARCH5 Targets FIS1 for proteasomal degradation; decreases 276

mitochondrial fission
GDAP1 Ubiquitylation by parkin (Lys50, Lys172, Targets GDAP1 for proteasomal degradation; 276

Lys173, Lys188, Lys190, Lys203, Lys206, enhances mitophagy

Lys207 , Lys214)
MFN1 Ubiquitylation by parkin Targets MFN1 for proteasomal degradation; 277

increases mitochondrial fission, activates mitophagy

Ubiquitylation by MARCH5 Favours fission 278

Phosphorylation by ERK (Thr526) Favours fission 279

Phosphorylation by PKC isoform-β2 (Ser86) Inhibition of mitochondrial fusion during ischaemia– 158

reperfusion injury
MFN2 Phosphorylation by PINK1 (Thr111, Ser442, Favours interaction of MFN2 with parkin; promotes 187

Tyr448) fission and mitophagy

Phosphorylation by PKA (Ser442) Affects vascular muscle cell proliferation 280

Ubiquitylation by parkin Regulates MFN2 levels and mitochondrial fusion 181

Ubiquitylation by MARCH5 Targets MFN2 for proteasomal degradation; inhibits 281

fusion
Phosphorylation by JNK (Ser27) Promotes recruitment of the ubiquitin ligase 159

HUWE1, leading to MFN2 ubiquitylation and

proteasomal degradation; inhibits mitochondrial
fusion
OPA1 Cleavage by OMA1 Inhibits mitochondrial fusion 81

Cleavage by YME1L Required for mitochondrial fusion 282

Proteolysis by PARL Required to generate a pool of short OPA1 soluble in 82

the IMS and to form the OPA1 oligomer that inhibits

cristae remodelling
Acetylation (Lys936, Lys961) Lowers OPA1 GTPase activity 173

O-linked β-N-acetylglucosaminylation Increases mitochondrial fragmentation 175

(undefined Ser/Thr residues)

APC/C, anaphase-promoting complex/cyclosome; CaMKIα, calcium/calmodulin-dependent protein kinase Iα; CDK1,
cyclin-dependent kinase 1; DRP1, dynamin-related protein 1; ERK , extracellular-signal-regulated kinase; FIS1, mitochondrial
fission 1 protein; GDAP1, ganglioside-induced differentiation-associated protein 1; JNK , JUN amino-terminal kinase; MARCH5,
membrane-associated RING-CH protein 5; MAPL , mitochondrial-anchored protein ligase; MFN, mitofusin; OPA1, optic atrophy
protein 1; PARL , presenilin-associated rhomboid-like protein; PINK1, PTEN-induced kinase 1; PKA , protein kinase A ; PKC, protein
kinase C; YME1L , YME1-like ATPase.

BCL-2 family
A group of evolutionarily
conserved proteins that
harbour a BCL-2 homology
domain. Mostly known for their
regulatory role in programmed
cell death.
we decided to illustrate here only three examples
of bidirectional mitochondrial dynamics–signalling
cascade crosstalk.
Apoptosis, the stereotypical, genetically controlled
process of programmed cell death, is the paradigmatic
example of a cellular signalling cascade that requires the
OMM, leads to mitochondrial morphological changes
and is controlled by mitochondrial dynamics. The role
of mitochondria in apoptosis was identified when the
antiapoptotic protein BCL-2 was found associated with
the OMM24. Here, together with other members of the
BCL-2 family, BCL-2 controls OMM permeabilization
that is accompanied by mitochondrial fragmentation
and cytochrome c release25. Apart from regulating the

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Nucleoids
The literal meaning of this
term is ‘nucleus-like’; it refers
to a cluster of proteins and
mitochondrial DNA, not
surrounded by a membrane.
Nature Reviews | Molecular Cell Biology
formation of apoptotic pores, BCL-2 family members
can interact with and influence the activity of key
mitochondrial fusion and fission proteins26–28.
As another example, several A-kinase anchoring
proteins, which recruit cAMP-dependent serine/threonine-
specific protein kinase A (PKA) are associated with the
OMM, thus regulating cAMP signalling in time and
space29. This OMM association also leads to discrete
areas of increased PKA-dependent phosphorylation at the
OMM30, influencing the activity of several mitochondrial
dynamics proteins as we will see in detail later.
Finally, OMM localization of mitochondrial
antiviral-signalling protein (MAVS) is essential to mount
a response to viral infection. MAVS also regulates the
activity of the mitochondrial fusion protein mitofusin 1
(MFN1; see also later) to promote fusion, which supports
MAVS-mediated signal transduction8.
In addition to regulating signalling events at the
OMM, these three signalling cascades extend beyond
the OMM: BCL-2 family members also induce cristae
remodelling3; similarly, one of the PKA substrates is a
cristae biogenesis factor, MIC19 (ref.31) (see the next
section); MAVS is involved in regulating mitochondria–
ER contacts32. Overall, the OMM can be truly regarded
as the platform of mitochondrial integration within
cellular signalling.
Mitochondrial cristae dynamics
Mitochondrial cristae are dynamic structures that adapt
their architecture in response to physiological inputs and
in pathology, notably apoptosis. The organization of the
IMM into cristae, also known as cristae biogenesis, is a
complex process with multiple players. First, it can be
intrinsically caused by spontaneous forces generated
by lipid- and protein-driven membrane curvature33.
In addition, the OMM likely serves as a border to limit
the extension of cristae structures, while the protein-rich
matrix determines the minimum volume of the inner
compartments of the organelles. These ‘spontaneous’
organizers of cristae shape work in concert with specific
protein modulators of cristae architecture.
A key multiprotein complex regulating cristae bio-
genesis is the mitochondrial contact site and cristae
organizing system (MICOS). This large heterooligomeric
protein structure of the IMM is composed of MIC10,
MIC12, MIC19 MIC25, MIC26, MIC27 (also known as
MOMA1 and APOOL) and MIC60 (also known as mito-
filin), organized in two independent protein assemblies,
MIC27–MIC10–MIC12 and MIC60–MIC19, linked
via MIC19 (ref.34). The composition of MICOS is not
still completely defined. For example, QIL1 (encoded
by C19orf70) was recently identified in human cells as
an essential MICOS component35. A strong hint that
MICOS is associated with cristae morphogenesis comes
from evolutionary analyses indicating that MICOS
components are found exclusively in organisms with
cristae-containing mitochondria36.
Functionally, each MICOS component exerts a
specific effect on membrane shape, and together they
can generate the curvature changes required for cris-
tae biogenesis. MIC10 forms a hairpin in the mem-
brane and harbours a glycine-rich motif required for
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oligomerization37,38. MIC60 is the largest and a core
MICOS complex component39,40. The MICOS complex
disassembles in MIC60-deficient mitochondria of yeast
and human cells, where cristae disconnect from the
inner boundary membrane. In addition, these cells are
characterized by OXPHOS defects, abnormal distribu-
tion of nucleoids and impaired mitochondrial translation.
The conserved function of MIC60 on cristae formation
and/or maintenance of cristae junctions39–41 was fur-
ther reinforced by elegant experiments whereby fungal
Mic60 was shown to induce membrane deformation
in liposomes in vitro and it was sufficient to cause invag-
inations that resemble nascent cristae in bacterial mem-
branes following ectopic expression42,43. However, these
invaginations are not fully formed cristae, raising the
question of how a completely formed cristae structure is
achieved in mitochondria of higher organisms. One pos-
sibility is that MIC60 cooperates with other proteins that
shape cristae architecture. For example, MIC60 can inter-
act with two other proteins that repeatedly affect cristae
shape (see also later), F1Fo-ATP synthase via MIC27 (ref.44)
and the dynamin-related protein (Box 1) OPA1 (Mgm1p
in yeast) via MIC19 (ref.45). While the bacterial membrane
harbours the ATP synthase, a classical dynamin-related
protein like OPA is not found in prokaryotes, suggesting
that perhaps the OPA1–MIC60 interaction occurred later
in evolution and could have been the driving force for
cristae shaping.
At the cristae edge, F1Fo-ATP synthase is organized
in dimers, which can further assemble into oligomers.
The long double rows of ATP synthase dimers along the
cristae ridges have been observed across species46,47. ATP
synthase dimers have been proposed as crucial drivers
of cristae morphology, because their formation can bend
lipid bilayers. In turn, the elastic membrane conforma-
tion favours their association into rows. In line with this
idea, deletion of the ATP synthase dimerization sub­
units causes loss of invaginations, with the IMM being
inflated into an onion-like or balloon-like shape46,48.
Moreover, ATP synthase inhibitor factor 1 (IF1) neg-
atively impacts ATP synthase oligomerization, at the
same time disturbing cristae organization and reduc-
ing their density during physiological and pathological
conditions49. It should be noted, however, that mutated
ATP synthase dimerization subunits lead to altered
IMM dynamics, impaired OXPHOS, membrane poten-
tial reduction and disruption of lipid microdomains50.
Thus, whether ATP synthase assemblies directly impact
on cristae curvature is still unclear.
Another key regulator of cristae architecture is
OPA1 (refs51,52), which is important for cristae junc-
tion formation and maintenance, and also, as will be
discussed in the following section, independently reg-
ulates mitochondrial fusion. In yeast and mammalian
cells, Mgm1/OPA1 ablation or alteration leads to cris-
tae disorganization and widening of cristae junctions.
Biochemically, OPA1-driven cristae biogenesis corre-
lates with the stability of high molecular weight com-
plexes of OPA1 (notably, these complexes are disrupted
on apoptotic stimulation, which drives apoptotic IMM
remodelling, facilitating cytochrome c release; see also
later). Accurate measurements indicate that the stability
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Box 1 | Membrane shaping by dynamin-related proteins
Dynamin-related proteins (DrPs) are a group of GtPases whose main function is to
shape biological membranes. Members of the DrP family include dynamins, dynamin-
like proteins, Mx dynamin-like GtPases, optic atrophy protein 1 (OPa1), mitofusin1
(MFN1), MFN2 and guanylate-binding proteins229.
DrPs undergo GtP-dependent conformational changes that drive their oligomerization
and endow them with the capability to induce membrane fission. their structure includes
a GtPase domain and a GtPase effector (GeD) domain, which together form a flexible
intramolecular unit named ‘bundle signalling element’. rearrangement of this element
promotes nucleotide-dependent GtPase domain dimerization, translating GtP binding
into self-assembly of the DrPs into spirals/rings229. these conformational changes favour
GtP hydrolysis, which in turn narrows the adjacent dynamin rings, induces DrP rotation
and membrane constriction up to the formation of a hemifusion membrane that
undergoes scission230.
One of the best studied DrPs is dynamin 1, which is essential for endocytosis.
this is a stepwise process that leads to the formation of omega-shaped invaginations
underneath the plasma membrane, which are ultimately released into the cytoplasm
as excised vesicles. endocytosis starts on interaction of adaptor proteins with
transmembrane proteins protruding from the lipid bilayer towards the cytosol.
These complexes form scaffolds for the recruitment of clathrin triskelion units at the
neck of endocytic vesicles, and then trigger membrane deflection up to the formation
of coated pits engulfing a molecular cargo, and provide an anchor for Bin/amphiphysin/
rvs (Bar) motif-containing proteins such as endophilin and amphiphysin231.
The synergistic activity of these proteins controls membrane remodelling by supporting
dynamin 1 oligomerization into α-helices and twisting of its GtPase domain, followed
by dynamin 1 oligomers wrapping around budding endocytic vesicles. these events
result in GtP cycle-dependent membrane fission229,232–234. this mechanism of membrane
fission is conserved between DrPs, no matter whether it occurs on the plasma or
intracellular membranes.
the activity of DrPs that act on intracellular membranes is not restricted to fission,
with some DrPs facilitating fusion and tubulation (that is, generation of tubular
invaginations or projections). through these activities, DrPs control the morphology
of different organelles. sometimes various DrPs act to remodel the same organelle, as
occurs for DrP1, OPa1 and mitofusins in mitochondria. alternatively, a single protein
can act on two organelles. For example, atlastin 1 is necessary for the morphogenesis
of both the Golgi apparatus and the endoplasmic reticulum, while DrP1 shapes both
peroxisomes and mitochondria235,236.
DrP-mediated membrane remodelling impacts on the function of individual
organelles, on their interconnection and on cell physiology and fate. in light of these
different functional consequences, mutations in the genes encoding DrPs have been
associated with various human disorders. For instance, mutations in SPG3A, encoding
atlastin 1 (ref.237), cause hereditary spastic paraplegia. as another example, mutated
forms of the endoplasmic reticulum-shaping protein dynamin 2 have been associated
with inherited peripheral neuropathy (Charcot–Marie–tooth disease)238. Charcot–
Marie–tooth disease-causing mutants affect dynamin 2 binding to membranes or
membrane curvature generation, ultimately altering its fission-related functions.
Diseases associated with mutations in the genes encoding DrP1, mitofusins and OPa1
are shown in Table 1.
of these complexes directly correlates with the cristae
junction diameter and cristae lumen width; similarly,
OPA1 overexpression decreases cristae lumen width,
tightening the cristae53,54. Mechanistically, one study
showed that Mgm1 can form helical filaments on the
inside of membrane tubes with the shape and dimen-
sions of cristae junctions. They further suggested that a
dynamin-like power stroke (Box 1) in such a left-handed
helical assembly on the inside of a membrane tube
would constrict its diameter55. Cristae formation and
Bin/amphiphysin/Rvs (BAR) stability can also be explained by homotypic interactions
domain between Mgm1/OPA1 on opposing membranes47,56. For
Domains that mediate protein OPA1, it has been proposed that this tethering of mem-
dimerization, first discovered in
three protein classes named
branes and cristae maintenance involves a protease-
Bin, amphiphysin and Rvs cleaved, soluble OPA1 (so-called short OPA1 (S-OPA1))
(BAR). present in the intermembrane space that serves as a
bridge between unprocessed, membrane-bound OPA1
(so-called long OPA1 (L-OPA1)) molecules (see also the
next section).
Proteomic analysis further identified MIC60 as well
as multiple ATP synthase subunits as components of
the OPA1 high molecular weight complexes associ-
ated with cristae remodelling45,53,54, raising the question
of whether OPA1 controls cristae shape alone or with
these other players. Formal epistatic analyses revealed
that in mammals OPA1 lies upstream of both MIC60
and ATP synthase dimerization in the regulation of
cristae shape53,54. Similarly, in yeast lacking Mgm1, ATP
synthase oligomerization is impaired52,57,58, lending
further support to the central role of OPA1 in sculpt-
ing cristae. However, this model lacks formal proof,
for example, in heterologous models such as bacteria.
Lastly, there is evidence that cristae remodelling via
OPA1 is coupled to the formation of ER–mitochon-
dria membrane contact sites, whereby signals from the
OMM are relayed to OPA1, inducing its proteolytic pro-
cessing, via the OMM protein mitofusin 2 (MFN2; see
also later).
Finally, it is conceivable that other factors partici-
pate in cristae biogenesis and maintenance. For exam-
ple, protein FAM92A1, which carries a Bin/amphiphysin/
Rvs (BAR) domain and resides at the matrix side of the
IMM, can generate membrane curvature through pref-
erential interaction with negatively charged phospholip-
ids such as phosphatidylinositol 4,5-bisphosphate and
cardiolipin and hence orchestrate cristae shape59. The
relationships between this and the other newly discov-
ered cristae shape factors and MICOS, ATP synthase and
OPA1 are unclear and warrant further investigation.
Mitochondrial fusion and fission
Fusion and fission are key events regulating mitochon-
drial morphology that need to be balanced to support
normal mitochondrial function and prevent disease60.
Accordingly, several human diseases have been associ-
ated with mutations in the regulators of these dynam-
ics (Table 1). Several excellent reviews summarize our
current understanding of mitochondrial fission and
fusion61–63. Here, we provide the reader with the basic
knowledge of these processes, which is needed to under-
stand how signalling pathways can impinge on mito-
chondrial morphology and how mitochondrial form
and function are linked.
Mitochondrial fusion. In mammalian cells, the fusion of
mitochondria is regulated by two mitofusins — proteins
belonging to the dynamin-related family of large
GTPases (Box 1): MFN1 and MFN2 (the encoding gene
is mutated in Charcot–Marie–Tooth disease type 2A)64
located in the OMM (of note, there is only a single
mitofusin in yeast, Fzo1p)65 and OPA1 (mutations of
the encoding gene are associated with dominant optic
atrophy)66,67 located in the IMM68 (Fig. 2,Table 1).
MFN1 and MFN2 display a very high degree
of homology and similar structural organization69.
However, genetic and biochemical studies highlighted
that the two mitofusins display different functions:
MFN1 is a core component of the fusion reaction
www.nature.com/nrm
 Reviews

ER
(cross section)
INF2 Calcineurin-dependent
Actin dephosphorylation
OMM
Spire 1C
DRP1
Mitochondrion DRP1 Phosphorylation
Calcium

Calcineurin DRP1 receptor

ER
Ca2+ influx

Fusion Fission

MFN1

MFN1 Short OPA1 Cardiolipin

GTPase domain Long OPA1
Transmembrane domain OMM
HR2
OMM
HR1
IMM IMM Protease
Matrix
OPA1 proteolytic processing

Fig. 2 | The mitochondrial life cycle involving fusion and fission. Fission and fusion cooperate to regulate mitochondrial
morphology and in extension its function allowing the mitochondrial network to adapt to the needs of a cell and to
external cues (Fig. 1d). Fission is primarily orchestrated by dynamin-related protein 1 (DRP1). DRP1 is phosphorylated on
Ser637 by protein kinase A , which maintains DRP1 in the cytoplasm. Fission occurs when DRP1 is dephosphorylated by
calcineurin and recruited to the mitochondrial surface (where it binds to its receptors). This has been shown to occur at sites
where the endoplasmic reticulum (ER) wraps mitochondria. Here, DRP1 oligomerizes and induces GTP hydrolysis-mediated
membrane constriction. The activity of DRP1 is supported by actin polymerization at the ER–mitochondria interface
mediated by the actin-nucleating proteins inverted formin 2 (INF2) and formin-binding protein spire 1C. This actin
filament accumulation could drive initial mitochondrial constriction that supports subsequent DRP1 polymerization.
The ER–mitochondria contact sites are also a functional platform for the transmission of Ca2+ signals from the ER to
mitochondria, which supports cristae remodelling, amplifies cytochrome c release and fuels mitochondrial apoptosis (Fig. 3b).
Fusion relies on two GTPases residing at both the outer mitochondrial membrane (OMM) and the inner mitochondrial
membrane (IMM), mitofusin 1 (MFN1) and optic atrophy protein 1 (OPA1), respectively. Fusion starts with the docking of
two MFN1 molecules in trans, likely through the HR2 domain or GTPase domain; this association induces conformational
changes that drive GTP hydrolysis by MFN1 molecules, leading to fusion of the two OMMs. In the IMM, the unprocessed
OPA1 form (known as long OPA1) interacts with lipid cardiolipin in trans, whereby OPA1 is fusion competent.
This association is promoted in the presence of short OPA1, which is generated by proteolytic degradation of long
OPA1. Another mitofusin, MFN2, is also required for fusion, but its mechanism in this process is elusive (it is an established
tether between mitochondria and other organelles, prominently the ER (Box 2)).

together with OPA1, whereas the exact role of MFN2
in fusion remains elusive and it has been shown to par-
ticipate in mitochondrion–mitochondrion interaction,
as well as in juxtaposition of mitochondria with other
organelles (in particular with the ER)68,70,71, which will
be further discussed later. The crystal structures of
a minimal MFN1 (formed by the predicted GTPase
domain and the distal part of the carboxy-terminal tail)
suggest that MFN1 functions as a tether between fusing
mitochondria. In support of the tethering role of MFN1,
the minimal MFN1 also dimerizes in a GTP-dependent
manner, leading to artificial membrane clustering72.

Nature Reviews | Molecular Cell Biology

Reviews
Rhomboid protease
Intramembrane serine
proteases that share a
common catalytic domain
composed of six
membrane-spanning segments.
Whether the same is true for full-length MFN1 is still
to be determined.
The role of OPA1 in mitochondrial membrane
fusion was established in the early days of mitochondrial
dynamics, and the function ascribed was coordination
of OMM and IMM fusion. Around the same time, the
role of OPA1 in mitochondrial cristae remodelling was
also discovered51,68, raising the question of how a single
protein can mediate these two distinct processes. The
elucidation of the crystal and cryo-electron microscopy
(cryo-EM) structures of yeast Mgm1 now provides struc-
tural support for its different functions. A key feature of
the quaternary structure of Mgm1 is its organization in
right- or left-turned helical assemblies. Right-turned
assemblies at the inner boundary membrane can exert
a pulling force on the membrane, eventually leading to
bending and fusion. Left-turned assemblies inside the
cristae can conversely constrict the membrane, thereby
diminishing the cristae lumen55. The possibility to adopt
both turns is therefore an economical solution to a pro-
tein which participates in both fusion and cristae remod-
elling. Whether the same organization is conserved for
OPA1 is unclear, especially because of the limited degree
of homology between the two molecules. Another key
aspect of OPA1 function that remains unresolved despite
the elucidation of Mgm1 structure is how its direct
interaction with MFN1 (ref.56) can coordinate OMM
and IMM fusion68. A plausible model involves the coor-
dinated formation of OMM fusion pores mediated
by GTP hydrolysis-stimulated MFN1 oligomerization73
followed by IMM fusion by right-turned helical assem-
blies of OPA1, perhaps somehow activated by MFN1.
Finally, fusion depends on the appropriate balance
between L-OPA1 and S-OPA1. In vitro studies revealed
that L-OPA1 establishes two types of interactions between
membranes: homotypic trans interaction between two
L-OPA1 molecules that are fusion incompetent; and
hetero­typic trans interactions between L-OPA1 and cardio­
lipin that are fusion competent (Fig. 2). Similarly to the
role of S-OPA1 in cristae biogenesis, addition of S-OPA1
to the trans L-OPA1–cardiolipin complex enhanced
membrane fusion74.
In yeast, Mgm1 is proteolytically processed by a sin-
gle enzyme: a mitochondrial rhomboid protease, Rbd1,
that generates a pool of short-form Mgm1 (refs75,76); this
processing as well as the presence of both long and short
forms of Mgm1 was found to be required for regulation
of IMM structure and for mitochondrial fusion56,77, sub-
stantiating the role of Mgm1/OPA1 proteolytic process-
ing in mitochondrial membrane dynamics. Mammalian
OPA1 is processed by multiple enzymes. The key enzyme
for generating S-OPA1 is YME1L1 (ref.78). In addition,
OPA1 is processed by the IMM peptidase OMA1, lead-
ing to mitochondrial fission and fragmentation on mito-
chondrial dysfunction79–81; these mechanisms might also
be used during cell death (see the section Crosstalk with
cell function). Whether S-OPA1 generated by OMA1-
mediated processing has a direct profission role79 or
whether the changes in mitochondrial morphology
observed on OMA1 activation are caused by an imbal-
ance between the L-OPA1 form and the S-OPA1 form,
which, like for Mgm1, are both required for efficient
mitochondrial fusion77, is still unclear. Mammalian
OPA1 might also be processed by the Rbd1p orthologue
presenilin-associated rhomboid-like protein (PARL;
whether this processing occurs directly or indirectly is a
matter of debate)82–84. PARL-mediated processing is not
essential for the generation of S-OPA1 but participates in
its further maturation. When PARL is deleted, S-OPA1
is still produced, but the fraction soluble in the inter-
membrane space is lacking. This specific fraction of
S-OPA1 does not participate in mitochondrial fusion
but participates in the formation of the OPA1 high
molecular weight oligomers that maintain cristae junc-
tions82. Overall, processing of OPA1 has extensive impact
on mitochondrial dynamics, and how exactly different
forms of OPA1 function awaits further refinement.
Mitochondrial fission. The fission of mitochondria
is primarily carried out by dynamin-related protein 1
(DRP1; Dnm1 in yeast)85, which translocates from the
cytosol to mitochondria, binding to its OMM partners
(called receptors): mitochondrial fission factor (MFF),
mitochondrial dynamics protein of 49 kDa (MID49),
MID51 and mitochondrial fission 1 protein (FIS1)86–89
(Fig.  2) . Following this binding, DRP1 oligomerizes
and drives scission. Mechanistic insights into DRP1-
mediated scission have been gained recently through
cryo-EM analysis of MID49/MID51–DRP1–GTP
complexes. This analysis revealed that GTP binding to
DRP1 induces formation of linear polymers on the mito-
chondrial membrane stabilized by the interaction with
the receptors. Subsequent GTP hydrolysis was associa­
ted with polymer shortening while curling into closed
rings with an inner diameter of 16 nm, well in the range
of complete mitochondrial constriction90.
In yeast, Fis1 is mainly engaged to recruit Dnm1 to
the mitochondrial membrane (of note, yeast Fis1 does
not directly bind Dnm1 but acts as a membrane adapter
for additional mitochondrial division proteins Mdv1 and
Caf4, which do not have homologues in mammals)91–93.
By contrast, mammalian mitochondria show a normal
phenotype after FIS1 deletion86. Yet, FIS1 overexpres-
sion leads to mitochondrial fragmentation87 — an effect
that could be secondary to other FIS1 functions such as
regulation of mitochondrial Ca2+ fluxes and function94,
enhanced interaction with lysosomes (which can mark
sites of mitochondrial fission)95 and inhibition of the
mitochondrial fusion machinery96. This latter effect,
however, remains contentious94,96, raising questions on
its contribution to the mitochondrial fragmentation
observed on FIS1 overexpression. Instead, MFF seems
to prevail over the other DRP1 receptors in mammals.
However, it should be noted that the phenotype of
the Mff-knockout mouse is much milder than that
of the Drp1-knockout mouse (Drp1 is also known as
Dnm1l)60,97. It could be that other DRP1 receptors can
compensate for MFF absence98 or that the pathological
unbalance between fusion and fission is less pronounced
in Mff-knockout mice as compared with Drp1-knockout
mice60. There is also evidence that DRP1 oligomerizes
even in the absence of DRP1 receptors, but in this case
structural studies indicate nucleotide-independent con-
striction of membranes to a final diameter of 30–70 nm
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Iron–sulphur clusters
Metal prosthetic groups
synthesized in mitochondria
and acting as cofactors to
catalyse several redox
enzymatic activities.
Nature Reviews | Molecular Cell Biology
(ref.99),which is not sufficient to drive the complete
mitochondrial constriction, suggesting a requirement
for other DRPs (Box 1) to complete scission100 (although
the role of other DRPs beyond DRP1 in mitochondrial
fission remains contentious)101,102.
As mentioned already, DRP1 is a cytosolic pro-
tein that must translocate to mitochondria to induce
fission. This translocation depends on phosphorylation–
dephosphorylation of Ser637 of DRP1. This modifica-
tion, which is mediated by PKA, decreases DRP1 GTPase
activity and leads to mitochondrial elongation due to
unopposed mitochondrial fusion103,104. The same site
can be dephosphorylated by the Ca2+-dependent phos-
phatase calcineurin, which was shown to drive DRP1
mitochondrial association and fission105. Although the
role of these phosphorylation–dephosphorylation events
in regulating mitochondrial fission was recently ques-
tioned106, cryo-EM analysis of the MID49/MID51–DRP1
complex predicts that Ser637 phosphorylation inhibits
the DRP1–receptor association90, indicating that dephos-
phorylation is indeed required to translocate DRP1 to
mitochondria (Fig. 2).
Finally, it is important to note that the process of
mitochondrial fission is much more complex than DRP1-
mediated membrane scission. As will be discussed in the
following section, mitochondrial fission sites are tightly
associated with ER tubules, which together with actin
cytoskeleton support membrane constriction (Fig. 2).
Interactions with other organelles
In the context of mitochondrial membrane dynamics,
it is important to consider that the OMM is engaged in
an extensive network of interactions with membranes
of other organelles establishing membrane contact sites.
The notion that mitochondrial dynamics could be
regulated by contact sites with other organelles stemmed
from two observations: that the fusion protein MFN2
also tethers mitochondria to the ER71, and, as mentioned
earlier, that mitochondrial fission spatially localizes at
sites of proximity to the ER107. This organization of the
fission platforms by the ER is reverberated by the finding
that in mammalian cells the putative DRP1 receptor FIS1
regulates contacts with the ER108 and with lysosomes95,
further highlighting the tight connection between mem-
brane dynamics and interorganelle contact sites. We will
now provide an overview of the different interactions
between mitochondria and other organelles, how they
are involved in regulation of mitochondrial dynamics
and how this could impact on mitochondrial function.
ER–mitochondria interactions. The interaction
between mitochondria and the ER is to date the best
studied type of a membrane contact site. This inter-
face was first discovered when ER membrane patches
were biochemically isolated attached to the OMM109
and named mitochondria-associated ER membranes.
Mitochondria-associated ER membranes are tethered
to mitochondria by protein bridges, establishing mito-
chondria–ER contact sites (MERCs)110,111 (Box 2). A key
MERC tether is MFN2, which by localizing at both
the ER and the OMM can homo-oligomerize (tether-
ing hetero-oligomers between MFN2 and MFN1 were
Reviews
also described) to physically link the two organelles.
Bridging of ER and mitochondria also can be mediated
by the interaction of ER-resident vesicle-associated
membrane protein-associated protein B (VAPB)
with OMM protein tyrosine phosphatase-interacting
protein 51 (PTPIP51) (Box 2). It has also been reported
that spatial dynamics of both organelles are coupled and
depend on acetylated microtubules112.
As mentioned earlier, spatially, mitochondrial fis-
sion occurs at sites of proximity to the smooth ER,
which wraps around mitochondria (Fig.  2). At these
membrane contact sites, DRP1 cooperates with the
actin-nucleating proteins inverted formin 2 (INF2) and
formin-binding protein spire 1C, which causes actin
accumulation that precedes DRP1 recruitment to sites
of fission. This actin filament accumulation could drive
initial mitochondrial constriction that supports subse-
quent DRP1 polymerization113,114 (Fig. 2). These MERCs
also allow the delivery of Ca2+ to mitochondria, which
activates IMM constriction in a DRP1-independent
manner to complete fission115 and can also drive mito-
chondrial apoptosis (see also the section Crosstalk
with cell function). In addition to regulating fission,
MERCs are important sites for the exchange of lipids
between ER and mitochondria116. Loss of lipid homeo-
stasis at MERCs was shown to lead to abnormal mito-
chondrial architecture, with markedly shortened cristae
and mitochondrial hyperfusion, leading to dysfunction of
mitochondrial respiration and premature senescence117
(in accordance with the regulation of both processes by
mitochondrial dynamics; see the section Crosstalk with
cell function). We expect that further, in-depth character-
ization of the ER–mitochondria interface will reveal novel
regulators of mitochondrial morphology and function, as
well as their interplay.
Plasma membrane–mitochondria interactions. Beyond
MERCs, functional crosstalk between mitochondrial
membrane dynamics and other membranes is now start-
ing to emerge. For example, in mammary stem cells, mito-
chondria can be tethered to the plasma membrane by the
binding of MFN1 to the plasma membrane-associated
pool of protein kinase C isoform-ζ, which allows asym-
metric distribution of fused mitochondria to regulate
stem cell fate decisions (see also the section Crosstalk
with cell function)118. Mitochondria–plasma membrane
contacts are also involved in the regulation of Ca2+ influx
from the extracellular medium, which is controlled by
MFN2 (ref.119). It is important to note that while the
mitochondria–plasma membrane tethering machin-
ery is somewhat understood in yeast, where a handful
of tethers have been identified120, it remains elusive in
mammalian cells. We expect that its characterization will
prompt the discovery of additional crossroads between
mitochondrial shape and function and how they are
regulated by plasma membrane-derived signalling.
Interactions between endosomes/lysosomes and mito-
chondria. Mitochondria are the site of biogenesis of
iron–sulphur clusters, which requires a constant supply
of iron, which is taken up by endocytosis121,122. Super-
resolution microscopy revealed interactions between
Reviews

Box 2 | Mitochondrial juxtaposition with the er: a prototypical membrane contact site
Mitochondrial contacts with the endoplasmic reticulum (er) — mitochondria–er contact sites (MerCs) — are one
of the best studied membrane contact sites110, and several functions have been associated with them (see the figure).
the existence of MerCs has been evidenced by partial colocalization of fluorescently labelled mitochondria and er239,
isolation of er membranes linked to mitochondria (mitochondria-associated er membranes (MaMs))109 and the observation
of electron-dense, rod-shaped structures connecting the two organelles110,240,241.
For a long time, it has been known that MerCs host microdomains of high Ca2+ concentration. it is now established that
one of the key functions of MerCs is mediating Ca2+ transfer between the er and mitochondria. energy-dependent
mitochondrial Ca2+ uptake, described in the 1960s, was explained by Mitchell’s chemiosmotic theory192. substrate
oxidation drives Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCu), which sustains the activity of three matrix
dehydrogenases, connecting mitochondrial Ca2+ handling and physiology242. rapid entry occurs at sites of proximity
between mitochondria and the er. Ca2+ transfer is mediated by the inositol trisphosphate receptor (iP3r)–GrP75–
voltage dependent anion channel (vDaC) complex, while additional MaM-associated proteins, such as FuN14
domain-containing protein 1 (FuNDC1)243 and disrupted in schizophrenia 1 protein (DisC1) modulate Ca2+ uptake244.
However, the first MaM-associated protein was phosphofurin acidic cluster sorting protein 2 (PaCs2), which has been
shown to impact mitochondrial morphology and lipid synthesis245. indeed, enzymes fundamental for phospholipid
biosynthesis reside at MerCs, and conversion of phosphatidylserine into phosphatidylcholine requires the mutual
exchange of their intermediates246. another MerC protein is mitofusin 2 (MFN2), which resides both in the er and in the
outer mitochondrial membrane (OMM). er- and OMM-resident forms of MFN2 can oligomerize to physically link these
organelles71,247 in several tissues, from pro-opiomelanocortin (POMC) neurons, where MFN2-dependent MerCs control
leptin resistance221, to the heart, where MFN2 deficiency uncouples mitochondria from the sarcoplasmic reticulum,
resulting in impaired bioenergetics248, to glioma stem cells, where it regulates glycan levels249. this suggests that MFN2
acts as a bona fide tether250. Nevertheless, two independent reports concluded that MFN2 deletion increases er–
mitochondria tethering251,252. MFN2 domain organization resembles that of other proteins of the dynamin superfamily
involved in membrane tethering. it is therefore difficult to rationalize a direct antagonist of this function. Perhaps, under
the conditions studied in these reports, the increased tethering is due to compensatory effects mediated by, for example,
er stress253, or increased expression of other tethers. MerCs can be also tethered by the interaction of er-resident
vesicle-associated membrane protein-associated protein B (vaPB) with OMM protein tyrosine phosphatase-interacting
protein 51 (PtPiP51)254. in cells lacking the vaPB–PtPiP51 complex, autophagy is impaired255,256, in line with the evidence
that MFN2-tethered MerCs are a source of autophagosome membranes257. whether MerC-derived autophagosomes
can engulf any cargo or are specific for one type of autophagy (erphagy, mitophagy, pexophagy, etc.) remains to be
defined. the existence of tethering complexes might suggest that contact sites are stable; however, we can infer that
they can quickly undergo remodelling following tissue-specific metabolic needs or stresses110. MerC plasticity likely
relies on regulatory partners such as the keratin filament-binding protein trichoplein (tCHP; also known as mitostatin),
which interacts with and inhibits MFN2 (ref.258). regulatory components do not necessarily need to be proteins:
ceramides, for example, can bind vDaC2 to regulate apoptosis by blocking vDaC2-mediated retrotranslocation
of the pore-forming proapoptotic protein BaX, thereby allowing its accumulation on mitochondria259.

ER
IP3R MFN2 PTPIP51

Autophagy DISC1 TCHP Lipid and

GRP75

phospholipid
Ca2+ PACS2
biosynthesis
homeostasis
FUNDC1
VAPB Mitochondrial
Apoptosis
morphology
OMM VDAC

Mitochondrion

Transferrin
An iron-binding glycoprotein
that controls the level of free
iron in the blood.
mitochondria and endosomes carrying iron-bound
transferrin123, indicating that mitochondria function-
ally engage in crosstalk with the endosomal system.
Cholesterol can also be transferred from endosomes
to mitochondria. The physical coupling of these
organelles might depend on the endosomal protein
MLN64: its amino terminus is anchored at the endo-
somal surface and its carboxy terminus (harbouring a
cholesterol-binding domain) faces the cytosol, being
available for OMM interaction and direct cholesterol
transfer to mitochondria124. These contacts can also be
regulated by certain cues, including pathological signals,
as shown by enhanced association between RAB5-
positive early endosomes and mitochondria during
oxidative stress. This association led to decreased apop-
totic potential of mitochondria, likely via protection (for
example, mediated by the transport of lipids and meta­
bolites between the organelles) and/or repair of damaged
mitochondria to preserve cell viability125. The impact of
mitochondria and their dynamics on the endosomal
system are currently unknown.
Lysosomes contribute to mitochondrial homeostasis
not only by mediating their clearance in stress/unhealthy
conditions but also by marking the sites of mitochondrial

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β-Oxidation
The catabolic process through
which fatty acids are degraded
in mitochondria to produce
acetyl coenzyme A.
Ceramide
A family of lipid molecules
composed of a fatty acid
conjugated to the 18-carbon
amino alcohol sphingosine.
Nature Reviews | Molecular Cell Biology
fission95. The lysosomal RAB7 GTPase is fundamental
to keep the two organelles in touch: its displacement by
RAB7 GTPase-activating protein TBC1D15, which asso-
ciates with FIS1, drives RAB7 inactivation, lowering the
extent of juxtaposition of mitochondria and lysosomes
and providing space for ER–DRP1-mediated fission
events95. Whether the mitochondria-shaping machin-
ery can locally influence lysosomal functions remains
to be elucidated.
Interactions between lipid droplets and mitochondria.
Juxtaposition of mitochondria and lipid droplets has
been described in adipose and skeletal muscle tissues,
and has been shown to be mediated by perilipin 5, which
resides at the surface of lipid droplets126. Mitochondria
associated with lipid droplets (also known as peri­droplet
mitochondria) display unique properties, including
increased bioenergetic capacity, lower ß-oxidation and
slower fission–fusion cycles127. Thus, it appears that the
interaction with lipid droplets has an inhibitory effect on
mitochondrial dynamics, perhaps by directly influenc-
ing the fusion–fission machinery, or by exposing its core
players to a steady flux of fatty acids or their derivatives
that might inhibit them, in similarity to MFF inhibition
by ceramide-derived sphingolipids128.
Interactions between peroxisomes and mitochondria.
Crosstalk between peroxisomes and mitochrodria is
supported by the shared metabolic processes (such as
β-oxidation of fatty acids and bile acid synthesis)129
as well as by the shared division machinery components
(DRP1, MFF and FIS1). Although the molecular details
of this crosstalk remain poorly uncharacterized, both
organelles engage in the formation of membrane contact
sites. Fzo1p, the yeast mitofusin, serves as a bona fide
tether between peroxisomes and mitochondria130, par-
alleling the mitochondria-tethering function of mam-
malian MFN2 with organelles other than mitochondria
such as the ER71 and melanosomes131. A handful of
other tethers between peroxisomes and mitochondria,
not related to mitochondrial dynamics, have also been
discovered, ranging from peroxisome protein Pex11 and
Mdm34, a component of the ER–mitochondria tether-
ing complex known as the ER–mitochondria encounter
structure (ERMES) in yeast, to ATP-binding cassette
subfamily D member 1 (ABCD1) and enoyl-CoA delta
isomerase 2 (ECI2; also known as ACBD2) isoform A in
mammals132–134. We expect that the discovery of the full
set of tethers between mitochondria and peroxisomes
will lead to a deeper understanding of the crosstalk
between mitochondria and their dynamics and perox-
isomes, providing new insights into the regulation of
cell metabolism.
Crosstalk with cell function
As mentioned earlier, the list of cellular processes
impacted by mitochondrial shape changes is long
and steadily growing (Fig. 1a). We will now provide an
overview of several examples of crucial cellular events
that are accompanied by mitochondrial dynamics.
We will discuss how these processes affect mitochon-
drial morphology, focusing on the many PTMs of
Reviews
mitochondria-shaping proteins (Table 2) and their links
to cellular signalling pathways; reciprocally, we will
also discuss how these cellular events are influenced by
changes in mitochondrial morphology.
Mitochondrial morphology and apoptosis. Historically,
cell death has been the first cellular process where
changes in mitochondrial shape have been implicated135.
However, this observation remained anecdotal until the
discovery of the role of DRP1-dependent mitochondrial
fragmentation2 and of cristae remodelling in cytochrome c
release and apoptosis3 (Fig. 3a,b). We then learned the
basic tenets of how mitochondrial dynamics are con-
trolled in the course of cell death and how they impact
cell death execution.
During the initial stages of apoptosis, proapoptotic,
pore-forming proteins, BAX and BAK, translocate to
discrete foci on mitochondria, which colocalize with
DRP1 and MFN2 (but not other mitochondria-shaping
proteins) and subsequently become mitochondrial
fission sites. It was then proposed that these foci are
associated with block of fusion, which — by perturb-
ing the balance between fusion and fission — results in
apoptotic mitochondrial fragmentation136.
Mitochondrial fission is fundamental for apop-
tosis2. BAX and BAK promote DRP1 stabilization at
fission sites, preventing its normal cycling between
the cytosol and mitochondria, and ultimately initiat-
ing apoptotic fragmentation137. This mitochondrial
stabilization is associated with DRP1 sumoylation,
occurring at eight different sites and catalysed by the
mitochondrial-associated SUMO E3 protein ligase
MAPL138,139 (Table 2). During cell death, DRP1 sumoy-
lation and stabilization on mitochondrial membranes
favours mitochondrial fission and network fragmenta-
tion, but also contributes to establishment of a func-
tional platform for the transmission of Ca2+ signals from
the ER to mitochondria that support cristae remodel-
ling, amplify cytochrome c release and fuel mitochon-
drial apoptosis (Fig. 3a; see the next paragraph)137,140.
In the context of cell death, mitochondrial fission can
also be regulated by modulating DRP1 Ser637 phospho-
rylation–dephosphorylation. Because Ser637 dephos-
phorylation and DRP1 recruitment to mitochondria
depends on calcineurin, which is Ca2+ sensitive, it is not
surprising that several pathological conditions leading
to sustained cytoplasmic Ca2+ influx, such as apop-
tosis, can cause mitochondrial fragmentation 141–147.
Accordingly, calcineurin inhibition can be beneficial
in multiple conditions associated with elevated cell
death105,148–157.
Inhibition of mitochondrial fusion during apoptosis
has been linked to the activity of different kinases that
phosphorylate both mitofusins. MFN1 is phosphoryl-
ated by the mitogen-activated protein kinase cascade
member extracellular signal-regulated kinase on Thr562
(Table 2). This phosphorylation was shown to directly
inhibit fusion by perturbing MFN1 oligomerization
and mitochondrial tethering. Non-oligomerized MFN1
was then implicated in promoting BAK oligomeriza-
tion to favour mitochondrial permeabilization dur-
ing apoptosis. Inhibition of mitochondrial fusion was
Reviews

a b Mitochondrial fission
and permeabilization

Apoptotic
Hyperfusion • Increased membrane stimuli
potential
• Ca2+ accumulation

• Altered ultrastructure
• Cytochrome c redistribution
and release Cristae remodelling
Basal
condition
Apoptosis
Fission

Skipping
Starvation Unopposed cell death
fusion

Inhibition of autophagic
degradation
PKA-mediated
phosphorylation

RCC
d Fibroblast iPS cell Differentiated cell DIABLO
OXPHOS Glycolysis OXPHOS Disorganized RCC cAMP
OPA1 Calcium
OPA1 oligomer PKA
Cytochrome c DRP1

Increased Increased APAF1 Phospho-DRP1

fission and fusion
mitophagy Apoptosome Autophagosome
Caspase
Mitophagosome
IAP

Fig. 3 | changes in mitochondrial morphology impact on complex cellular
processes/behaviours. a | Mitochondrial fission is a hallmark of the early
steps of apoptosis2, and it is associated with altered mitochondrial
ultrastructure (cristae remodelling), leading to intramitochondrial
cytochrome c redistribution from cristae to the intermembrane space171
and release to the cytosol. Mitochondrial hyperfusion can precede fission
during apoptosis2 and can lead to mitochondrial Ca2+ overload212 and
mitochondrial ultrastructural damage that promotes cytochrome c release.
b | Mitochondrial ultrastructure plays a fundamental role in the control of cell
death. Apoptotic stimuli induce the activation of the proapoptotic
pore-forming proteins BAX and BAK (not shown), which mediate
mitochondrial outer membrane permeabilization (MOMP), allowing the
release of intramitochondrial metabolites and proteins, prominently
including two caspase activators: cytochrome c and direct inhibitor of
apoptosis protein (IAP)-binding protein with low pI (DIABLO; also known as
SMAC). Once in the cytosol, cytochrome c interacts with apoptotic
protease-activating factor 1 (APAF1), which induces the formation of the
apoptosome and subsequent activation of the caspase cascade; this is further
supported by proteins such as DIABLO, which sequesters caspase inhibitor
proteins. Besides MOMP, apoptosis induces mitochondrial fission and
associated Ca2+ influx into mitochondria (Fig. 2). BAX/BAK activation and Ca2+
influx promote destabilization of optic atrophy protein 1 (OPA1) oligomers at
cristae junctions, resulting in widening of the cristae. This promotes the
release of cytochrome c. c | Nutrient deprivation (starvation) induces a
response in which mitochondrial fusion plays a key role. Elongation of
mitochondria prevents their degradation by autophagy , thus preserving
metabolic fitness and preventing cell death. This regulation of mitochondrial
membrane dynamics occurs via increased cytosolic cAMP levels, which
activate protein kinase A (PKA), leading to dynamin-related protein 1 (DRP1)
Ser637 phosphorylation to inactivate mitochondrial fission. d | Mitochondrial
membrane dynamics regulate cell reprogramming into induced pluripotent
stem (iPS) cells as well as stem cell differentiation. Specifically , induction of
pluripotency is associated with mitochondrial fragmentation via regulation
of DRP1 phosphorylation and removal of mitochondria via mitophagy266.
By contrast, early steps of iPS cell differentiation are accompanied by
mitochondrial fusion. These changes in mitochondrial membrane dynamics
go hand in hand with metabolic changes: iPS cells are characterized by
reduced oxidative phosphorylation (OXPHOS) and rely mostly on glycolysis,
while in differentiated cells, OXPHOS is a prevailing mechanism providing
cellular energy. RCC, respiratory chain complex.

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Ischaemia–reperfusion
injury
Tissue damage occurring
especially in the heart on
coronary artery occlusion and
reperfusion on physicians’
intervention, for example,
by percutaneous coronary
intervention (formerly known
as angioplasty with stent).
Omegasomes
Omega-shaped organelles
which precede the formation
of autophagosomes.
Nature Reviews | Molecular Cell Biology
also observed during heart ischaemia–reperfusion injury
on phosphorylation of MFN1 by protein kinase C
isoform-β2 at Ser86 (Table 2), with detrimental effects
on mitochondrial function158. MFN2 is phosphorylated
by the stress-induced JUN amino-terminal kinase on
Ser27 (Table 2), ultimately leading to MFN2 ubiquityla-
tion and proteasomal degradation159. Conversely, in the
event of stress, oxidation of MFN2 at Cys684 — with
the formation of intramolecular disulfide bonds resulting
in MFN2 oligomerization — stimulates mitochondrial
fusion160,161. It would be interesting to understand the
hierarchic organization of these MFN2 modifications in
the course of cell death. For example, the massive DRP1-
dependent mitochondrial fission occurring during
apoptosis is preceded by mitochondrial hyperfusion2
(Fig. 3a): perhaps this hyperfusion could be an attempt to
protect mitochondria against apoptosis and removal via
autophagy (mitophagy) under stress and could involve
oxidative modifications of MFN2.
The second facet of mitochondrial morphological
shape changes during apoptosis is OPA1-dependent
cristae remodelling, whereby the neck of the cristae
widens, to promote cytochrome c release51,162,163 (Fig. 3b).
The consensus that cristae remodelling is required for
cytochrome c release28,49,164–168 was questioned by a report
placing cristae remodelling downstream of caspase acti-
vation and hence of cytochrome c release169. However,
independent studies showed that cristae remodelling
occurs in cells lacking BAX and BAK, the BCL-2 family
members essential to allow cytochrome c egress from
mitochondria163, as well as in cells where caspases are
inhibited170, further reinforcing that cristae remodelling
is required for efficient apoptotic cytochrome c release.
The precise mechanism by which cristae remodelling
is induced is still a matter of debate. Proapoptotic mem-
bers of the BCL-2 family can directly interact with OPA1,
causing the disassembly of the oligomers that correlate
with cristae tightness28. In a different mechanism, apop-
totic mitochondrial Ca2+ overload (caused among other
processes by the stabilization of the ER–mitochondria
interface) can also lead to cristae remodelling that
depends on the permeability transition pore140,171, a
Ca2+-dependent high-conductance IMM channel whose
opening can lead to osmotic swelling of mitochondria
and cristae distension172. Disassembly of OPA1 contain-
ing oligomers is also a hallmark of this pathway of cristae
remodelling, but it likely follows the osmotic distension
of the IMM. Another possibility is that during cell death,
OMA1 protease is hyperactivated — via mitochondrial
depolarization or accumulation of reactive oxygen spe-
cies (ROS)90,92, or via BAX/BAK activation146 — leading
to OPA1 cleavage and cristae remodelling. However,
whether OPA1 cleavage is sufficient to induce cris-
tae remodelling is unclear. Similarly, it is uncertain if
cristae remodelling requires also other components of
the fission machinery, such as MID49/MID51 (ref.170).
In addition to proteolysis, OPA1 is also subject to vari-
ous PTMs that include acetylation173, nitrosylation174 and
O-linked N-acetylglucosamine glycosylation175 (Table 2)
that have been associated with stress conditions. However,
it is thus far unclear if these PTMs are responsible
for OPA1 inactivation and for cristae remodelling.
Reviews
All in all, the vast literature supports an essential
role for mitochondrial membrane dynamics as core
mechanisms of cell death. It is thus not surprising that
mutations in mitochondria-shaping proteins can cause
various diseases associated with cell loss (Table 1).
Mitochondrial morphology and mitochondrial qual-
ity control. A natural ramification of the discovery
that cell death was linked to and controlled by mito-
chondrial shape changes was to understand how
mitochondrial membrane dynamics are involved
in mitochondrial quality control mechanisms, which
serve as means of adapting the mitochondrial network
to cope with insults. These events range from proteo-
lytic control of mitochondrial protein misfolding, to
transcriptional responses driven by transcription fac-
tors that can shuttle between mitochondria and the
nucleus to selective mitochondrial degradation by
autophagy, also known as mitophagy, and finally to
shedding of mitochondrial-derived vesicles (MDVs) or
mitochondrial-derived compartments (MDCs) (Box 3).
The interplay between mitochondrial dynamics and
quality control has been the focus of several excellent
reviews176–180. Here, we will focus our attention on key
regulatory mechanisms of quality control pathways that
pertain to mitochondrial membrane dynamics.
An important facet of quality control mechanisms
is the activation of proteolytic cascades, which function
to clear the cell of misfolded proteins and to allow their
replacement with newly synthesized polypeptides. One
important pathway of proteolytic degradation involves
the ubiquitin–proteasome system, which has emerged as
a prominent regulator of mitochondrial fusion. The first
evidence that mitochondrial fusion could be regulated
came from studies reporting proteasomal degradation of
the yeast mitofusin orthologue, Fzo1p, which is ubiquity­
lated and subsequently targeted to the proteasome by the
F-box protein Mdm30p. It was subsequently found that
Drosophila melanogaster mitofusin is the target of the
ubiquitin ligase parkin181 (the encoding gene is mutated
in autosomal recessive juvenile forms of Parkinson dis-
ease) which constitutes a crucial component of the mito-
chondrial quality control pathway involving removal of
mitochondria via mitophagy182,183. In flies, parkin directly
ubiquitylates Marf (but not Opa1 or Drp1) and its loss
leads to increased Marf abundance in vivo and concom-
itant elongation of mitochondria181. A similar mecha-
nism operates in mammalian dopaminergic SH-SY5Y
cells, where parkin ubiquitylates MFN1. It is noteworthy
that Parkinson disease-associated mutations impair this
parkin-mediated ubiquitylation of MFN1, which could
explain why mitochondria appear elongated in this cell
model of Parkinson disease184. Since these original dis-
coveries, the field has progressed considerably, and we
have come to appreciate that several OMM proteins are
ubiquitylated and that this is specifically linked to the
regulation of mitophagy185. This ubiquitylation is funda-
mental for the clearance of defective mitochondria as it
is a triggering signal for the mitophagic process. Other
crossroads between mitochondrial dynamics and auto-
phagy exist. For example, mitochondria supply mem-
branes for the formation of omegasomes, which occurs at
Reviews
Box 3 | MDVs and MDcs
the observation of small vesicles excising from mitochondria, named mitochondrial-
derived vesicles (MDvs), was first observed 10 years ago, and since then MDvs have
been established as yet another type of interorganelle communication. indeed, MDvs
can fuse with other subcellular compartments, including peroxisomes, endosomes and
lysosomes, thereby transferring mitochondrial proteins and lipids to these organelles179.
their mitochondrial origin was ascertained by detection of outer mitochondrial
membrane (OMM) proteins, such as mitochondrial-anchored protein ligase (MaPL),
inner mitochondrial membrane (iMM) proteins or, in some cases, even mitochondrial
matrix molecules, which can be found in the MDv membranes or lumen190,260,261. MDv
cargo, however, is not random: it is selectively chosen depending on the mechanism
that activates MDv biogenesis. For example, mitochondrial stress induced by reactive
oxygen species led to stimulation of MDvs particularly enriched in voltage-dependent
anion channel (vDaC; also known as mitochondrial porin), whereas chemical inhibition
of respiratory chain complexes induced biogenesis of MDvs carrying the core subunit of
respiratory complex iii. Mechanistically, MDvs detach from mitochondria independently
of dynamin-related protein 1 (DrP1)190,260,262, but require proteins that impinge on
mitochondrial dynamics, such as parkin and PiNK1, for MDvs directed to lysosomes
and members of the retromer complex, such as vPs35, for MDvs associated with
peroxisomes261. the exact roles of MDvs are not fully understood. However, on the
one hand, MDvs targeted to peroxisomes may allow transport of specific lipids and/or
proteins (including membrane-shaping proteins) from mitochondria. One the other
hand, lysosome-targeted MDvs could represent a means of quality control, whereby
damaged mitochondrial portions are removed before they could negatively impact on
their parental mitochondrion179. Likely, this mechanism would not suffice if the structure
and function of that individual organelle are compromised, requiring its entire removal
through mitophagy263.
apart from MDvs, mitochondria can also bud structures referred to as mitochondrial-
derived compartments (MDCs), which selectively accumulate both OMM and iMM
proteins and after release involving dynamin-mediated fission are degraded in the
lysosome. MDCs were described for the first time in yeasts: here, the MDC-mediated
degradation pathway is initiated in the presence of vacuole-driven mitochondrial
dysfunctions and could function in mitochondrial quality control, independently of (or
in parallel to) mitophagic clearance. the mechanism of this specific protein degradation
via MDCs is not known, but as shown in yeast, it relies on tom70 and tom71 — two
paralogues forming a component of the mitochondrial tOM complex involved in the
recognition and initial import steps for all mitochondrially directed proteins191.
although MDCs and MDvs might appear similar, they are not the same entity. First,
they are likely to engulf different cargos. second, MDCs require the fission machinery for
their release, while MDvs do not. third, they likely have different roles in mitochondrial
homeostasis, with MDCs primarily acting in selective protein clearance/degradation,
while MDvs could also mediate cargo exchange and thereby act as signalling entities.
Further studies will certainly clarify the mechanisms and physiological functions of MDCs
and MDvs as well as their eventual impact on pathological conditions, such as ageing.
sites of interaction of mitochondria with the ER, which,
as described earlier, also serve as sites for mitochondrial
fission. Reflecting this association, there is mounting evi-
dence that parkin ubiquitylates and inhibits the key ER–
Retromer complex mitochondria tether MFN2 (refs181,186), thus altering the
A coat-like complex that crosstalk between these two types of organelles (Box 2)
mediates the recycling of the and providing a means to modulate both mitophagy and
endosomal cargo into vesicles
moving back to the Golgi
mitochondrial membrane dynamics. It is interesting
apparatus. to note that beyond ubiquitylation, few other PTMs of
mitochondria-shaping proteins have been identified
5′-AMP-activated protein so far in the context of mitochondrial quality control,
kinase
with the notable exception of MFN2 phosphorylation,
(AMPK). A key protein kinase
that plays a critical role in which is a prerequisite for MFN2 ubiquitylation and
cellular homeostasis. By mitophagy187, and the phosphorylation of DRP1 recep-
phosphorylating a plethora tor MFF by 5′-AMP-activated protein kinase (AMPK),
of targets, it acts as a general which is also a prerequisite for mitochondrial fission and
switch to regulate cellular
functions such as glucose
elimination by mitophagy188.
absorption, fat oxidation and Because fission events are required for clearance of
mitochondrial biogenesis. damaged mitochondria through mitophagy, fission can
be potentially modulated by a plethora of additional
non-core proteins to regulate mitophagy. For exam-
ple, ganglioside differentiation associated protein 1
(GDAP1) has been classified as a ‘fission factor’ because
its overexpression leads to DRP1/FIS1-dependent
mitochondrial fragmentation 189. However, despite
these insights, we deem that the space of the regulation
of mitochondria-shaping proteins in quality control
mechanisms is truly open for discovery.
A recently emerging mechanism of mitochondrial
quality control involves the release of MDVs and the
generation of MDCs (Box  3). MDVs are small vesi-
cles that originate from mitochondria, engulf certain
cargoes and transfer them to other organelles, such as
lyso­somes and peroxisomes (Fig. 1c). MDVs also influence
mitochondrial membrane dynamics, from the structural
as well as the functional point of view. Structurally, they
contribute to membrane remodelling by excision of
mitochondrial membranes; functionally, they include
OMM, IMM and/or matrix proteins that could either be
targeted to lysosomes for degradation or translocated to
peroxisomes (with as of yet unclear consequences)179,190.
MDCs appear to be a novel route of mitochondrial qual-
ity control, mediating clearance of OMM and/or IMM
proteins following mitochondrial dysfunction191. While
MDVs and MDCs are certainly involved in mitochon-
drial quality control, to what extent they definitively
participate in the regulation of mitochondrial dynamics
remains to be clarified.
Mitochondrial morphology and metabolism. A further
field where mitochondrial dynamics are thought to have
a crucial role is the control of metabolism. Elongated
mitochondria are thought to be more bioenergetically
efficient. This concept perhaps stems from the observa-
tion that mitochondria fragment in the course of apop-
tosis, as we described earlier, which goes hand in hand
with the energetic crisis of cells undergoing cell death.
In any case, molecular determinants of bioenergetic
efficiency reside in the IMM and changes in mitochon-
drial morphology inevitably involve IMM remodelling21.
Indeed, mitochondrial architecture and function were
originally observed in isolated mitochondria undergo-
ing cycles of respiration and inactivity18. Mitochondria
are basically thermodynamic converters of energy
and operate according to the chemiosmotic theory of
Mitchell192 (Supplementary Box 1), but this key function
is often forgotten when mitochondrial involvement in
cell biology or in tissue function is being studied. The
chemiosmotic theory explains and rationalizes very
complex mitochondrial processes such as Ca2+ uptake
and extrusion or mitochondrial depolarization during
apoptotic cytochrome c release. It thus should come as
no surprise that several experimental observations of the
consequences of perturbed mitochondrial dynamics can
be clarified if one keeps this role as energy converters
in mind. The link between mitochondrial membrane
dynamics and mitochondrial metabolism is such an
example. The thermodynamic efficiency of mitochondria
is fixed, but respiratory chain supercomplexes can stream-
line mitochondrial electron transfer and respiration.
Notably, OPA1 overexpression can favour the assembly
www.nature.com/nrm

Chemiosmotic theory
The theory proposed by
Mitchell explaining ATP
synthesis by mitochondria.
The chemical energy of NADH
and FADH2 is converted by the
electron-transport chain into
an electrochemical proton
gradient across the inner
mitochondrial membrane
(IMM), whose free energy is
in turn used to catalyse the
phosphorylation of ADP by the
IMM-bound ATP synthase.
Respiratory chain
supercomplexes
Assembly of distinct
respiratory chain complexes
that guarantees efficient ATP
production while reducing
electron loss and production
of reactive oxygen species.
Epithelial–mesenchymal
transition
The process through which
epithelial cells lose their
characteristics of adhesion
and polarity and acquire those
typical of mesenchymal stem
cells, including differentiation
abilities
Nuclear factor of activated
T cells
(NFAT). A family of
transcription factors that can
translocate into the nucleus
in response to stimuli that
enhance intracellular Ca2+
levels. Once in the nucleus,
they induce transcription of
target genes.
Nature Reviews | Molecular Cell Biology
and stability of respiratory chain supercomplexes by
tightening mitochondrial cristae21. In addition, through
interactions with IMM solute transporters, OPA1
can also act as a sensor of metabolic changes, thereby
allowing adaptation of cristae shape and respiration to
cellular needs193.
Mitochondrial fission is also regulated to couple
mitochondrial morphology to the energetic status of the
cell. This process occurs at the level of DRP1 and of its
main receptor MFF. In conditions of starvation, DRP1
is phosphorylated on Ser637 in a PKA-dependent fash-
ion and this leads to unopposed mitochondrial fusion
and ultimately in longer mitochondria4,5, which, in turn,
prevents their autophagic degradation and supports
survival of starving cells (Fig. 3c). By contrast, fission is
induced by phosphorylation mediated by AMPK, the
master kinase that is activated when cellular ATP levels
drop. AMPK associates with mitochondria, which may
allow it to rapidly sense the changes in the energy status
of a cell and adapt mitochondrial function (by regulat-
ing its biogenesis, quality control and dynamics) to the
energy needs194. AMPK directly phosphorylates two sites
on MFF, Ser155 and Ser172, which were shown to facili-
tate mitochondrial fission downstream of mitochondrial
dysfunction caused by mitochondrial respiration inhi-
bition. This mechanism could support the removal of
damaged mitochondria via autophagy or induce apop-
tosis in cells with severely dysfunctional mitochondria188.
Similarly, in the context of ischaemia–reperfusion injury,
which leads to bioenergetic insufficiency by several
converging mechanisms195, MFF phosphorylation is
promoted by serine/threonine kinase casein kinase-2α
(CK2α), leading to mitochondrial fission and cell death
(it is though unclear whether MFF is a direct substrate
of CK2α)196.
Mitochondrial morphology and the cell cycle. Mitochon­
drial shape must also be regulated during the cell cycle
to allow appropriate partitioning of mitochondria to the
daughter cells. Indeed, while during interphase mito-
chondria appear long and tubular, during early mitosis
they are fragmented in a DRP1-dependent fashion197.
Cell cycle progression depends on a complex interac-
tion among different signal transduction cascades that
work as checkpoints for the subsequent mitotic steps
and for cytokinesis. The three most important protein
families involved in mitosis are the cyclin-dependent
kinases (CDKs; kinases that bind cyclin-like proteins,
which are responsible for the transition between cell
cycle stages), the Aurora family (overall controlling
chromatid segregation, the formation of mitotic spin-
dle, and centrosome separation) and kinases of the
anaphase-promoting complex/cyclosome (APC/C;
a multiprotein E3 ubiquitin ligase complex that targets
mitotic proteins for degradation, promoting anaphase).
Notably, cell cycle-dependent changes in the mitochon-
drial shape are mediated by the activity of members of
all these cell cycle controller families.
In particular, CDK1 (in complex with cyclin B) acts
downstream of Aurora A to phosphorylate DRP1 on
Ser585 and Ser616 (Table 2), which promotes the recruit-
ment of DRP1 to the mitochondrial surface, thus leading
Reviews
to mitochondrial fission in early mitosis198. This mitotic
fragmentation of the mitochondrial network favours bal-
anced mitochondrial redistribution into daughter cells
and ensures their proper function in bioenergetics199.
Mitotic mitochondrial fragmentation is also important
to shut down the oxidative mitochondrial metabolism
in dividing cells; this metabolic rewiring allows glucose
and glutamine-derived metabolic intermediates to be
used for efficient biosynthesis of macromolecules, such
as DNA and lipids, required for cell division200–202.
By contrast, when cells exit mitosis, DRP1 is ubiqu­
itylated by APC/C (Table 2), which targets DRP1 for
proteasomal degradation, thereby shifting mitochon-
drial dynamics in interphase cells towards elongation
to support normal cell metabolism203,204. In addition,
as we described earlier when discussing the regulation
of mitochondrial fission during cell death, DRP1 can
be stabilized on the mitochondrial surface by sumoyl-
ation. This DRP1 sumoylation is antagonistically reg-
ulated by the SUMO protease SENP5 (ref.205), which
resides primarily within the nucleoli and during G2/M
phase translocates to mitochondria to desumoylate
DRP1 (ref.206). Ultimately, these modifications allow
the fine-tuning of mitochondrial morphology during
cell cycle. Specifically, the dynamic regulation of DRP1
activity by degradation and stabilization on mitochon-
dria exemplifies how distant cell signalling cascades
(cell cycle progression and cell death) can converge on
the same mitochondrial dynamics effector to modu-
late mitochondrial shape and ultimately the complex
decision between life and death.
Mitochondrial morphology and cell differentiation.
Differentiation and pluripotency are complex cell
responses that previously were not considered to be
influenced by mitochondrial membrane dynamics but
were considered rather to be controlled at the level of
gene expression. This view changed with the discovery
that mitochondrial fusion is required for heart devel-
opment by controlling NOTCH signalling and sub­
sequent cardiomyocyte differentiation7. In the following
years the concept of the involvement of dynamic changes
in the mitochondrial network in cell fate decisions was
consolidated and extended.
Mitochondrial dynamics were observed to deter-
mine the differentiation potential of induced pluri­
potent stem cells. Specifically, the first steps of induced
pluripotent stem cell differentiation are accompanied
by increased mitochondrial fusion, whereas if fission
prevails, pluripotent stem cells fail to differentiate118,207
(Fig.  3d) . Mitochondrial hyperfusion (induced by
epithelial–mesenchymal transition) appears to correlate
with increased self-renewal potential in mammary
stem cells118. Similarly, mitochondrial fusion orches-
trates a NOTCH-dependent self-renewal transcrip-
tion programme in neural stem cells6. Furthermore,
cell fate decisions in haematopoietic stem cells208 and
during osteoclastogenesis209 have been shown to be
regulated by MFN2, which was essential to control
transcription activity of nuclear factor of activated T cells
(NFAT). Finally, in embryonic stem cells mitochon-
drial fusion activation was necessary and sufficient to
Reviews
Naive embryonic stem cells
Embryonic stem cells of the
preimplantation blastocyst that
have the potential to generate
all the somatic cell lineages.
Primed embryonic stem
cells
Embryonic stem cells (from
post-implantation epiblast) that
can self-renew and differentiate.
Senescence-associated
secretory phenotype
The release of factors such as
inflammatory cytokines, growth
factors and proteases from
senescent cells.
Integrated stress response
A generally prosurvival stress
response induced on exposure
of the cell to either internal
factors such as accumulation
of unfolded protein leading to
endoplasmic reticulum stress
or external factors such as
nutrient deprivation and viral
infection.
ATF4
Cyclic AMP-dependent
transcription factor 4 plays
a key role in cell response to
stress stimuli, mostly by
promoting cell survival.
Mitokine
A cytokine produced by tissues
undergoing mitochondrial
stress and affecting other cell
types in an endocrine or a
paracrine manner. Mitokines
include, for example, FGF21
and GDF15.
Leptin
This term derives from Greek
leptos (‘thin’); it refers to a
hormone that inhibits hunger.
Pro-opiomelanocortin
(POMC) neurons
Neurons located in the
arcuate nucleus within
the hypothalamus; they
produce a polypeptide
named pro-opiomelanocortin,
whose proteolysis generates
several peptide hormones
(including α-melanocyte-
stimulating hormone and
adrenocorticotropic hormone).
ER stress
A set of intracellular pathways
activated by the cell to cope
with abnormal accumulation
of unfolded proteins in the
lumen of the endoplasmic
reticulum (ER).
drive the transition from naive embryonic stem cells to
primed embryonic stem cells210. Molecularly, in several
cases, Ca2+ appears to link changes in mitochondrial
dynamics with altered stem cell differentiation. For
example, during cardiomyocyte differentiation, mito-
chondrial fusion is required to lower entry of Ca2+ from
the extracellular space and limit NOTCH signalling7.
Similarly, in haematopoietic, neuronal and osteoclast
progenitors, changes in the shape of mitochondria and/or
their interaction with the ER impact on NOTCH and
NFAT because of sustained cytoplasmic Ca2+ loads6,208,209.
Lastly, in induced pluripotent stem cells, MFF over­
expression and increased fission also increase cytosolic
Ca2+ concentrations, leading to hyperactivation of Ca2+/
calmodulin-dependent kinase II and degradation of
the master regulator of stem cell biology β-catenin207.
Notably, mitochondrial dynamics influence Ca2+ sig-
nalling by multiple mechanisms. For example, MFN2
can control ER–mitochondria Ca2+ transfer and hence
the amplitude of cytosolic Ca2+ transients, but also the
molecular machinery that allows refilling of the intra-
cellular Ca2+ stores71,119. By contrast, in the absence of
mitochondrial fission, mitochondria take up excess Ca2+
(refs211,212), thereby lowering cytoplasmic Ca2+ transients.
Thus, it is impossible to conclude that, for example,
mitochondrial fission promotes increased cytoplasmic
Ca2+ levels whereas mitochondrial fusion lowers them,
and the link between dynamics and Ca2+ transients must
be addressed on a case-by-case basis.
It is also interesting to note that overall, these studies
report effects of mitochondrial shape on differentiation
or pluripotency but do not address how changes in mito-
chondrial dynamics are embedded in these complex cas-
cades. In other words, whether key factors that regulate
differentiation and pluripotency operate by means other
than transcriptional regulation of mitochondria-shaping
proteins208 is currently unknown. This is perhaps due to
the very nascent nature of research in this field and to the
current mostly correlative links between mitochondrial
shape and stem cell fate regulation.
Mitochondrial morphology and cell senescence. A very
recent development in the cellular biology of mito-
chondrial dynamics is their key, yet only partially
elucidated, role in senescence. Although senescence
can be broadly defined as the state in which cell pro-
liferation is irreversibly arrested, it should not be con-
sidered as a uniform process; rather, different types of
tissue-specific senescence pathways exist. In addition
to the cell intrinsic (replicative) senescence, charac-
terized by telomere shortening due to reiterated rep-
licative cycles and chronic DNA damage response,
senescence can also be caused by oxidative stress, radia-
tion or oncogenic factors. Changes in the shape and/or
mass of mitochondria appear to underlie both types
of senescence. In human endothelial cells undergoing
intrinsic or radiation-induced senescence, mitochondria
appear extremely elongated, due to downregulation of
DRP1 and FIS1 (refs213,214). In this context, as well as
in oncogene-mediated senescence213, mitochondrial
OXPHOS seems to be a key player in senescence induc-
tion. This is likely because mitochondrial respiration can
be a source of ROS (Supplementary Box 1), which can
cause DNA damage, leading to enhancement of ROS
production, DNA damage response and activation of a
transcription programme to induce mitochondrial bio-
genesis and senescence-associated secretory phenotype213.
In addition to increased oxidative metabolism, mito-
chondrial hyperfusion would also impede mitophagy,
eventually leading to accumulation of dysfunctional
mitochondria and to increased ROS production215.
In line with this, depletion of these organelles can
reverse most of the phenotypes associated with
radiation-induced senescence, including enhanced ROS
production and senescence-associated secretory pheno-
type. All in all, we think that senescence triggers mito-
chondrial fusion, at least in some specific senescence
pathways or tissue contexts. However, it is unclear if this
process is required for senescence and whether it is of
any relevance in vivo. Similarly, it is unknown whether
changes in mitochondrial morphology trigger senes-
cence only by enhancing ROS production. We expect
that the connection between mitochondrial morphology
and senescence will be extensively explored in the future,
especially given the interest in senescence-modulating
drugs in ageing and cancer.
Roles in organismal homeostasis
The availability of molecular tools to control mitochon-
drial shape allowed us to understand that the impact
of the form–function relationship of these organelles
extends over the cellular boundaries — changes in the
physiology of a certain cell type modifies its crosstalk
with surrounding cells, thus influencing the whole organ
and even organism physiology and, in some cases, lead-
ing to pathological conditions or ageing. For example,
the drop in muscle OPA1 levels observed in seden-
tary elderly individuals can be modelled in mice with
inducible OPA1 muscle deletion. In this model, lack of
muscle OPA1 leads to systemic metabolism changes
and to senescence of distant epithelial tissues by acti-
vating an integrated stress response and ATF4-dependent
muscle production and secretion of fibroblast growth
factor 21 (FGF21), which functions as a mitokine216–218.
Similarly, abnormal mitochondrial elongation caused by
artificial or pathological DRP1 ablation in hippocampal
neurons led to increased ATF4 expression levels and
finally neuronal FGF21 synthesis219. The discovery that
mitochondrial shape is embedded in systemic signalling
was surprising, because the observed transcriptional
modifications and systemic signals occurred before any
detectable mitochondrial dysfunction216, a finding reca-
pitulated in other settings where FGF21 was produced
before mitochondrial function was affected220.
Another relevant example of how mitochondrial
dynamics can control homeostatic functions is the
connection between MFN2, leptin resistance and
obesity. Specific ablation of MFN2 in hypothalamic
pro-opiomelanocortin (POMC) neurons that respond to
leptin to control appetite impaired both the morpho­
logy of mitochondria and their interactions with the ER.
This elicited ER stress, resulting in leptin resistance, and
finally severe obesity221. The cellular and systemic meta­
bolic control exerted by MFN2 has also been reported
www.nature.com/nrm
 Reviews

Brown adipocytes
Cells that compose the brown
adipose tissue, enriched in
mitochondria and
characterized by high
thermogenic potential.
Alveolar type 2 epithelial
cells
One of the two cell types that
build the alveolar epithelium,
responsible for surfactant
synthesis and secretion.
in brown adipocytes. Specific ablation of MFN2 in these
cells decreased not only mitochondrial length but also
the extent of the interaction of mitochondria with lipid
droplets and cell size. The higher adiposity and body
weight that characterizes this experimental model
can be explained by considering that reduced contact
between the two organelles likely reduces the transfer
of fatty acids from lipid droplets to mitochondria, and
hence halts their utilization as an energy source dur-
ing β-oxidation in favour of their storage, even with a
normal diet222.
The fission–fusion balance appears fundamen-
tal also for the physiology of lungs and muscle. In the
first case, mitochondrial fusion is required in alveolar
type 2 epithelial cells for production of surfactant, a lipo-
protein complex composed of several phospholipids and
cholesterol necessary to reduce surface tension within
alveoli and preserve their structure. Ablation of MFN1
or MFN2 indeed impaired alveolar phospholipid syn-
thesis and caused spontaneous onset of lung fibrosis223.
In the skeletal muscle, mitochondrial fission determines
myofibre mass by regulating their survival: mice sub-
jected to transient (duration of 50 days) DRP1 ablation
were characterized by muscle atrophy and functional
decline, which was associated with changes to mito-
chondrial morphology (bigger but fewer mitochondria),
functional decline of mitochondria and mitochondrial
Ca2+ overload, leading to myofibre death211.
Conclusions and perspectives
The field of mitochondrial membrane dynamics has
expanded tremendously since its inception less than
15 years ago. We think that this is mostly due to the
realization that mitochondrial membrane dynamics are
embedded in cell signalling networks and has impor-
tant cellular functions (shape–function relationship)
and that disturbed dynamics of mitochondrial mem-
branes are linked to several common diseases (Table 1).
Nevertheless, despite intense research in this exciting
area, several questions remain open. For example, a
deeper understanding of the mechanisms and regulation
of molecules involved in fusion and fission is required.
This will call for identification of new players and char-
acterization of the structure of already identified ones,
as well as of PTMs and the dynamics of large protein
complexes involved in mitochondrial morphology.
One important avenue for future research is to under-
stand how these mechanisms adapt to different meta-
bolic and signalling states of the cell. Similarly, the field
awaits screens to comprehensively map structural teth-
ers and regulators of the interfaces between mitochon-
dria and other organelles, as well as discovery screens to
identify other essential proteins of the fusion and fission
machinery. Last, but not least, identification of small
molecules able to control mitochondrial dynamics/
shape through chemical compound screenings and bio-
chemistry approaches is currently being undertaken by
several laboratories224–226.
We expect that the information ensuing from these
studies will be used to expand our understanding of the
relationship between mitochondrial shape and func-
tion, including its roles in regulating cell metabolism,
signalling networks (such as those involved in cell death,
immunity and stress responses) and even gene expres-
sion through mitochondria–nuclear communication227.
It will also open up avenues for therapeutic modulation
of mitochondrial dynamics in pathological conditions,
including the associated congenital disorders224–226, dis-
eases linked to cell death such as neurodegeneration and
stroke224–226 and also cancer228.
Published online xx xx xxxx

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Acknowledgements
Research in the L.S. laboratory is supported by AIRC
IG19991, Italian Ministry of Education, University and
Research PRIN 2017BF3PXZ, Fondation Leducq TNE15004,
Muscular Dystrophy Association RG 603731 and Cariparo
Foundation SIGMI. Research in the M.G. laboratory is sup-
ported by CARIPARO Starting Grant 2016 AIFbiol and Unipd
STARS Consolidator FIRMESs.
Author contributions
M.G. and L.S. conceptualized, wrote most of and edited the
article. A.P. and C.G. wrote subsections. All authors approved
the final content.
Competing interests
The authors declare no competing interests.
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Supplementary information
Supplementary information is available for this paper at
https://doi.org/10.1038/s41580-020-0210-7.
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