698391

research-article2017
TUB0010.1177/1010428317698391Tumor Biology X(X)Maycotte et al.

Review
Tumor Biology

Mitochondrial dynamics and cancer May 2017: 1­–16 

© The Author(s) 2017
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DOI: 10.1177/1010428317698391
https://doi.org/10.1177/1010428317698391
journals.sagepub.com/home/tub

Paola Maycotte1,2, Alvaro Marín-Hernández3,

Miriam Goyri-Aguirre2, Maricruz Anaya-Ruiz2, Julio Reyes-Leyva2
and Paulina Cortés-Hernández2

Abstract
Cancer is among the leading causes of death worldwide, and the number of new cases continues to rise. Despite recent
advances in diagnosis and therapeutic strategies, millions of cancer-related deaths occur, indicating the need for better
therapies and diagnostic strategies. Mitochondria and metabolic alterations have been recognized as important for
cancer progression. However, a more precise understanding of how to manipulate mitochondria-related processes for
cancer therapy remains to be established. Mitochondria are highly dynamic organelles which continually fuse and divide
in response to diverse stimuli. Participation in the aforementioned processes requires a precise regulation at many levels
that allows the cell to couple mitochondrial activity to nutrient availability, biosynthetic demands, proliferation rates,
and external stimuli. The many functions of these organelles are intimately linked to their morphology. Recent evidence
suggests an important link between mitochondrial morphology and disease, including neurodegenerative, inflammatory
diseases and cancer. Here, we review recent advances in the understanding of mitochondrial dynamics with a special
focus on its relationship to tumor progression.

Keywords
Mitochondria, cancer, mitochondrial fusion, mitochondrial fission

Date received: 28 September 2016; accepted: 23 December 2016

Introduction
Mitochondria are often considered the cell’s powerhouse,
not only due to their essential role in the production of
adenosine triphosphate (ATP) through oxidative phospho-
rylation (OXPHOS) but also because of their crucial role
in other biochemical pathways such as pyrimidine and
purine biosynthesis, heme synthesis, the regulation of
nitrogen balance in the urea cycle, gluconeogenesis, ketone
body production, and lipid degradation and elongation.1,2
Emerging evidence has also demonstrated that mitochon-
dria play an important role in the regulation of cell signal-
ing, either serving as a scaffold for protein–protein
interactions or by regulating the levels of intracellular
messengers such as Ca2+ or reactive oxygen species (ROS).
Our understanding of mitochondrial dynamics, biogene-
sis, and degradation has dramatically increased in recent
years and evidence has shown that alterations in these pro-
cesses are linked to diverse pathological states including
cancer. Mitochondrial integrity is fundamental for survival
in response to energetic, environmental, and genotoxic
stressors. Despite a clear understanding of the importance of
mitochondrial dynamics, its precise role in the clinical out-
come of cancer patients remains to be established. In this
regard, increasing evidence suggests a potential utility of
diverse mitochondria-related parameters for cancer diagno-
sis and treatment, but the role of mitochondria in cancer
development or progression is not simple. Here, we describe
1CONACYT-Centro de Investigación Biomédica de Oriente, Instituto
Mexicano del Seguro Social, Puebla, México
2Laboratorio de Biología Celular, Centro de Investigación Biomédica de
Oriente, Instituto Mexicano del Seguro Social, Puebla, México
3Departamento de Bioquímica, Instituto Nacional de Cardiología
Ignacio Chávez, México, México
Corresponding author:
Paola Maycotte, CONACYT-Centro de Investigación Biomédica de
Oriente, Instituto Mexicano del Seguro Social, Km 4.5 Carretera
Atlixco-Metepec, 74360 Puebla, México.
Email: pmaycottego@conacyt.mx

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2 Tumor Biology
Figure 1.  Mitochondrial morphology and cellular processes
that have been related to them. Mitochondrial dynamics
are the result of a delicate balance between mitochondrial
fusion (characterized by the presence of long interconnected
tubules) and fission (characterized by small, fragmented
mitochondria). Diverse cellular functions have been associated
with mitochondrial morphology, as shown in the figure and
reviewed in the text.
the current knowledge of the processes regulating mito-
chondrial shape and function and review recent studies on
their role in tumorigenesis and cancer progression, focusing
on the potential use of mitochondrial biomarkers for cancer
detection and prognosis as well as on the possibility of tar-
geting mitochondrial dynamics for cancer therapy.
Mitochondrial fusion and fission
Our view of mitochondrial dynamics has dramatically
changed in the past years. Once considered to be a rigid
structure, mitochondria are now known to be organelles
that migrate throughout the cell, fuse, divide, and undergo
regulated turnover through mitochondrial autophagy or
mitophagy. Mitochondria continually divide and fuse,
even in resting cells where the mitochondrial network is
formed by a mixture of long and interconnected tubules.3–5
In some cells, they fuse together in a connected network,
whereas in other cells or under different circumstances,
mitochondria convert into a large number of small frag-
ments. Fibroblast mitochondria, for example, are usually
long filaments, whereas hepatocyte mitochondria are more
uniformly spheres or ovoids.3 The many functions of mito-
chondria are intimately linked to their morphology, and
there is a delicate balance between the fusion and fission
events, which allows proper mitochondrial function in the
cell.
Unopposed fission causes extensive mitochondrial
fragmentation, which has been generally associated with
cellular metabolic dysfunction and disease. However, con-
tinuous fusion results in a hyperfused network, which
counteracts metabolic insults, preserves cellular integrity,
and protects against autophagy.6 Thus, balanced fusion and
fission events shape mitochondria to meet cellular meta-
bolic demands and to regulate the removal of damaged
organelles. Besides being involved in the maintenance of
normal cell functions as the distribution of mitochondria
during cell growth, cell division, and differentiation, mito-
chondrial dynamics has recently been considered as a cor-
nerstone for the maintenance of cellular fitness since
alterations in fusion and fission events have been closely
linked to states of health and disease (Figure 1).5,6
The molecular machinery regulating mitochondrial
dynamics comprises large dynamin-like guanosine triphos-
phatases (GTPases) mediating the fusion and fission of
both outer mitochondrial membrane (OMM) and inner
membrane (IMM; Figure 2). OMM fusion is regulated by
mitofusins 1 and 2 (MFN1 and MFN2), which are required
for the maintenance of a reticular mitochondrial network
in cells.7 Mitofusins function through homo- and hetero-
typic interactions, and their synthesis is regulated by tran-
scriptional and post-transcriptional mechanisms (Figure
2).6 The transcriptional mitochondrial coactivators phos-
phatidylglycerol phospholipase C-1-alpha and beta (PGC-
1-α and β), which regulate mitochondrial biogenesis and
the expression of the respiratory complex machinery, have
also been involved in the regulation of mitochondrial
dynamics through control of gene expression.8,9 In this
regard, treatment of mice with resveratrol, a known activa-
tor of the protein deacetylase sirtuin 1 (SIRT1), decreased
PGC-1α acetylation and increased its activity. These
effects led to the induction of mitochondrial biogenesis
and increased mitochondrial size in skeletal muscle, con-
ferring metabolic advantages like increased aerobic capac-
ity in vivo.6 Also, PGC-1-β has been proposed to induce
mitochondrial fusion by increasing the transcription of
Mfn2 through estrogen-related receptor alpha (ERRα)
coactivation.9
Proteasome-mediated degradation of mitofusins is reg-
ulated by ubiquitylation and phosphorylation in response
to cellular stimuli.6 In general, mitofusins are degraded
during apoptosis, while decreased proteasomal degrada-
tion induces mitochondrial fusion and cell viability
(Figure 2). Deletion of either mitofusins or abrogation of
GTPase activity prevents mitochondrial fusion, inducing
the fragmentation of mitochondria in cultured cells.
Moreover, tissue-specific deletion of mitofusins in the
central nervous system, heart, muscle, or liver compro-
mises metabolic and organ function, highlighting their
importance at both the cellular and organismal levels.6
Mitochondrial phospholipids have also been shown to be
important for mitochondrial membrane fusion. It has been
suggested that local alterations of the phospholipid composi-
tion on the OMM may induce membrane curvature or desta-
bilize membrane bilayers to promote fusion or fission.6,17 In
this regard, phosphatidic acid (PA), a phospholipid that can
Maycotte et al. 3

Figure 2.  Molecular machinery involved in the shaping of mitochondria. Mitochondrial shape is regulated by a family of GTPases
with structural homologies to dynamin proteins. Mitofusins are the GTPases required for OMM fusion and they are regulated by
ubiquitylation and phosphorylation. The E3-ubiquitin ligase PARKIN marks both MFN1 and MFN2 with ubiquitin (ub) regulating
their activity and levels. However, the deubiquitylase USP30 antagonizes PARKIN activity promoting mitochondrial fusion.
PINK1 is a kinase able to phosphorylate ubiquitin chains on OMM proteins including MFN2 which can then recruit PARKIN.
Phosphorylation of MFN2 by JNK in response to cellular stress signals the recruitment of the E3-ubiquitin ligase HUWE1, triggering
MFN2 degradation by the proteasome. Also, miR-140, which can be induced by oxidative or genotoxic insults, negatively regulates
MFN1 translation. The transcriptional coactivator PGC-1-β has been proposed to regulate mitochondrial fusion via Mfn2 and
other mitochondrial genes like OPA1. MitoPLD is a member of the phospholipase D family which is bound to the outer membrane
and converts cardiolipin to phosphatidic acid. This catalytic activity is required for mitochondrial fusion. In mammalian cells, the
major player of mitochondrial fission is DRP1 which has a cytoplasmic localization (inactive form) and reversibly associates with
OMM at sites of mitochondrial division, where the fission occurs preferentially at ER-contact regions. DRP1 is subject to several
post-translational modifications in response to cellular cues. Phosphorylation of DRP1 at Ser637 represents the signal that controls
protein translocation from the mitochondria to the cytoplasm. Following mitochondrial depolarization, a rise in cytosolic Ca2+
activates cytosolic calcineurin (CaN) that dephosphorylates DRP1 on Ser637, inducing its translocation to mitochondria. CaN itself
is subject to translational regulation by miR-499 in a p53-dependent manner. Conversely, protein kinase A (PKA), after cyclic
AMP activation, phosphorylates this residue, leading to the elongation of mitochondria and resistance to various pro-apoptotic
insults. DRP1 localization to mitochondria is a process requiring adaptors on the OMM (FIS1, MFF, MiD49, MiD51, and Mcl-1L).
The mitochondrial ubiquitin ligase MITOL/MARCH5 promotes mitochondrial division in a DRP1- and MiD49-dependent manner.
MITOL/MARCH5 also targets MFN1 and FIS1. The mitochondrial anchored protein ligase (MAPL) induces SUMOylation of DRP1
targeting it to mitochondria and accelerating mitochondrial fission. SUMOylation can be reversed by the SUMO protease SENP5.
During mitosis, CDK1/cyclin B phosphorylates DRP1 at Ser616 to induce mitochondrial fission and proper organelle segregation.
ERK2 can also phosphorylate DRP1 at Ser616 during MAPK-mediated transformation. Enforced expression of MTP18 correlates
with the recruitment of DRP1 to mitochondria. DRP1 can also be S-nitrosylated at Cys644 in response to an increase in NO
inducing mitochondrial fission. Finally, an interaction of DRP1 with phosphatidic acid (PA) restrains DRP1 fission activity and
shifts the balance toward mitochondrial fusion. OPA1 is involved in inner membrane processing. Alternative splicing of OPA1
gives rise to long forms (L-OPA) that are proteolytically cleaved to short forms (S-OPA) by inner membrane peptidases, OMA1
and YME1L. While L-OPA1 induces mitochondrial fusion and maintains tubular mitochondria, excessive accumulation of S-OPA1
can either induce mitochondrial fusion or accelerate fission and promote mitochondrial fragmentation. The IMM peptidase
YME1L constitutively cleaves OPA1 at the S2 site inducing mitochondrial fusion. However, OMA1 cleaves OPA1 at the S1 site
constitutively or in response to stress, inducing mitochondrial fragmentation. The expression of OPA1 is under transcriptional
control of the NF-κB transcription factor, which governs diverse aspects of cell division and metabolic reprogramming. Post-
translational modifications—P: phosphorylation; ub: ubiquitination; SUMO: sumoylation; PA: phosphatidic acid.6,7,10–16

generate negative curvature of lipid membranes, has an phosphatase decreases PA levels and induces mitochondrial
important role in mitochondrial fusion. Phosphatidic acid– fragmentation.17 However, mitoPLD, a mitochondrion-
preferring phospholipase A1 (PA-PLA1) or Lipin 1 localized phospholipase D able to produce PA from
4 Tumor Biology
cardiolipin, facilitates MFN-mediated fusion and ablation of
mitoPLD induced mitochondrial fragmentation in vitro.6
Inner membrane fusion is mediated by optic atrophy 1
(OPA1), another dynamin-like GTPase anchored to the
IMM and mostly exposed to the intermembrane space
(IMS).6 Multiple forms of OPA1 have been described,
which are the result of alternative splicing and proteolytic
cleavage by mitochondrial proteases that target OPA1 upon
dissipation of membrane potential, mitochondrial DNA
(mtDNA) loss, or induction of apoptosis.4 Alternative splic-
ing of OPA1 produces long isoforms (L-OPA1) that are
cleaved to short forms (S-OPA1) with different functions on
mitochondrial morphology (Figure 2).10,11 The expression of
OPA1 is under transcriptional control of the nuclear factor-
κB (NF-κB) transcription factor, which governs diverse
aspects of cell division and metabolic reprogramming.18
The inverse process of mitochondrial fragmentation or
fission has been observed in response to nutrient excess
and cellular dysfunction in cardiovascular and neuromus-
cular disorders, obesity, and cancer. In normal cells, mito-
chondrial fission facilitates the autophagic clearance of
mitochondria (mitophagy) and allows the adaption of
mitochondrial activities to physiological demands.6 OMM
fission is mediated by a cytosolic dynamin family member
dynamin-related protein 1 (DRP1) that translocates from
the cytosol and binds its receptors on the OMM (fission
protein 1 (FIS1), mitochondrial fission factor (MFF),
mitochondrial dynamics of 49 kDa protein (MiD49), and
mitochondrial dynamics of 51 kDa protein (MiD51)) often
at sites where mitochondria make contact with the endo-
plasmic reticulum.6 DRP1 forms spirals around mitochon-
dria, and GTP binding and hydrolysis promote a
conformational change in DRP1 that results in membrane
constriction to sever both IMM and OMM.3,6 DRP1 is
regulated post-translationally at different levels including
protein phosphorylation, sumoylation, ubiquitination, and
S-nitrosylation (Figure 2).12
Mitochondrial fission is essential for growing and divid-
ing cells to populate them with adequate numbers of mito-
chondria. Although it is less evident why mitochondrial
fission and fusion are also needed for non-proliferating
cells, it is probably due to fusion-induced complementation
between damaged mitochondria. This allows sharing of
RNA, protein components, and lipids with other mitochon-
dria and mitigation of the effects of mtDNA mutations
caused by environmental damage. While mitochondrial
fusion would prevent mitochondrial damage through com-
plementation, the lack of fusion would favor mitochondrial
degradation through autophagy.3 Thus, non-proliferating
neurons cannot survive without mitochondrial fission, and
two human diseases, dominant optic atrophy and Charcot–
Marie–Tooth disease type 2A, are caused by fusion defects.4
Mfn1 and Mfn2 knock-out mice die in utero, and although
mouse embryo fibroblasts (MEFs) derived from these mice
do survive in culture, some of their mitochondria display a
reduced mtDNA copy number and decreased membrane
potential, causing problems with ATP synthesis.6 Therefore,
although an organism is unable to develop normally without
mitochondrial fusion, some cells can survive without this
process. These differential requirements of mitochondrial
fusion for survival may stem from the distinctive need to
distribute mitochondria in large cells,19 from higher demands
on oxidative metabolism in different cell types and develop-
mental stages, or from demands on other functions that are
indirectly affected by fusion.3 In this regard, cancer cells
have been proposed to harbor altered mitochondrial metab-
olism, a phenomenon related to the increased glycolytic
activity in cancer cells known as the Warburg effect. It will
thus be interesting to understand how dependent are cancer
cells on mitochondrial fusion and fission and whether this is
particular to one type of cancer.
Mitochondrial shape is controlled by changes in metab-
olism. In general, mitochondria fuse when they are forced
to rely on oxidative phosphorylation by withdrawing glu-
cose as a carbon source, thus maximizing oxidative phos-
phorylation by stimulating complementation among
mitochondria. Fusion is also enhanced by treatments that
inhibit protein synthesis, by starvation, and by autophagy
induction. Starvation-induced autophagy may enhance
fusion by increasing reliance on oxidative phosphorylation
through the metabolism of lipids and proteins.3 More spe-
cifically, autophagy induced by starvation or mammalian
target of rapamycin (mTOR) inhibition induces increased
cyclic adenosine monophosphate (cAMP) and protein
kinase A (PKA) activation, which phosphorylates DRP1 (at
Ser637) and increases its cytoplasmic localization, leading
to unopposed mitochondrial fusion.20 Then, elongated
mitochondria are spared from autophagic degradation
(mitophagy). Conversely, when elongation is blocked dur-
ing starvation, mitochondria consume ATP provoking star-
vation-induced cell death.20 Mitochondrial fusion is
required for mtDNA maintenance, probably because it
allows metabolite and mtDNA exchange between mito-
chondria. Thus, mitochondrial fragmentation due to
impaired fusion is often accompanied by bioenergetic
defects due to a loss of mtDNA.21 In agreement with the
previous observations linking mitochondrial elongation to
cellular survival, stress stimuli leading to protein synthesis
inhibition or serum and amino acid deprivation has been
shown to produce stress-induced mitochondrial hyperfu-
sion (SIMH), defined as a highly interconnected network
that induces increased mitochondrial ATP production and
has been proposed to work as an adaptive pro-survival
response against stress.21 Importantly, this mechanism was
independent of MFN2, BCL-2-associated X protein (BAX)/
BCL-2 homologous antagonist/killer (BAK), and prohib-
itins but required L-OPA1, MFN1, and the IMM protein
stomatin-like protein 2 (SLP-2).21
Maycotte et al. 5
Cancer cell metabolism
In cancer, cellular metabolism may be subverted to support
tumor growth. For instance, glycolysis is upregulated in
almost all cancer cells since it is needed for the synthesis
of macromolecules that are required for active prolifera-
tion.22,23 This characteristic, known as the Warburg effect,
has found clinical utility for imaging of tumors using
18F-fluorodeoxyglucose (18F-FDG) which accumulates
in highly glycolytic cancer cells and can be visualized by
positron emission tomography.23 Moreover, this upregula-
tion in glycolysis is currently being explored for cancer
therapeutics utilizing the non-metabolizable glucose
analog 2-deoxyglucose to block glycolysis and cancer
growth.24 Warburg assumed that “aerobic glycolysis” was
a universal property of malignant cells and suggested that
cancer is caused by impaired mitochondrial metabolism.
However, further studies have challenged this idea, and
evidence supporting the idea that dysfunctional mitochon-
dria is the main cause of the Warburg effect is limited.25
So, although there indeed seems to be a diminished oxida-
tive metabolism in many tumor types, it has been shown
that tumor mitochondria do respire and produce ATP.
Evidence thus suggests that there is no oxidative phospho-
rylation to glycolysis switch but rather an upregulation of
glycolysis that has also been observed not only in cancer
cells but in rapidly proliferating normal cells due to the
temporary higher demands in metabolic material and
energy for completing the cell proliferation process.23,26
Evidence in support of a decreased oxidative metabo-
lism in cancer cells has been explained in several ways for
different tumor types, including decreased pyruvate trans-
porter activity, lower pyruvate oxidation, truncated Krebs
cycle, reduced transfer of reducing equivalents to mito-
chondria, lower mitochondrial content, or defective res-
piratory chain.26 Perhaps the most documented cause of a
partial inhibition of oxidative phosphorylation in tumor
cells is the Crabtree effect or the inhibition by high con-
centrations of glucose and other hexoses. Also, the acidic
pH induced by lactate generation may affect pH-sensitive
oxidative enzymes decreasing their function.26 A general
property of transformed cells with dysfunctional mito-
chondria is increased ROS production.27 Therefore, it has
been suggested that these cells might show a lower thresh-
old of sensitivity to ROS-induced apoptosis. In agreement
with this idea, therapies able to specifically target the res-
piratory chain to further elevate ROS production have
been proposed to be useful in cancer cells which show
elevated levels of ROS. Indeed, this has been shown with
mitochondrial inhibitors like mitocans, As2O3, antimycin
A, or rotenone in cancer cells with defective mitochondrial
function.27
However, although there are several examples of tumor
cell lines which certainly exhibit a decreased mitochon-
drial function, that observation does not seem to apply to
all tumor cell types. The contribution of glycolysis to the
total cellular ATP supply has been estimated to range
between 10% and 70% depending on the cell type,26 indi-
cating that some tumor cell lines have high levels of oxi-
dative phosphorylation and that this pathway might be the
predominant energy source. Regarding oncogene-medi-
ated cell transformation, most of the research in cancer
cell metabolism has focused on the increased glycolysis in
cancer cells. However, recent evidence indicates that
some tumor suppressor genes and oncogenes also have an
important role in the modulation of mitochondrial func-
tion to support carcinogenesis.
Metabolic effects of oncogenes and
tumor suppressors
Glycolysis is stimulated in hypoxic regions of the tumor
where oxygen levels are low. This occurs by the induction
of hypoxia-inducible factor 1 (HIF-1), which is considered
a master regulator for the initiation and maintenance of the
Warburg effect at the level of gene expression of glycoly-
sis-related enzymes and glucose transporters.22,23,28 HIF-1
induction can be triggered by the accumulation of ROS
produced by dysfunctional mitochondria or by Krebs cycle
metabolites like succinate that can inhibit HIF-1α prolyl
hydroxylases in the cytosol, leading to the stabilization
and activation of HIF-1α.22,23 Succinate accumulation in
mitochondria can be caused by mutations in succinate
dehydrogenase, which has been documented in a familial
predisposition to benign tumors.22 Interestingly, HIF-1
levels are high in certain tumors even under oxygen-rich
conditions, indicating that hormones or growth factors
might cause stabilization of HIF-1 expression and that it
has important roles in tumorigenesis.22,23 Additionally,
HIF-1 itself can also function as a negative regulator of
mitochondrial biogenesis and oxidative phosphorylation.
For example, HIF-1 activation upregulates several mito-
chondrial proteins including pyruvate dehydrogenase
kinase 1, which inhibits the conversion of pyruvate to
acetyl-CoA by pyruvate dehydrogenase resulting in
decreased mitochondrial respiration.22,29 HIF-1 activation
also inhibits MYC transcription and activates its degrada-
tion by the proteasome pathway. Since MYC is a positive
regulator of PGC-1α and PGC-1β, the mitochondrial coac-
tivators that regulate mitochondrial biogenesis and the
expression of the respiratory machinery, its repression by
HIF-1 results in the inhibition of mitochondrial biogenesis
and oxidative phosphorylation.30,31 Interestingly, the
human von Hippel–Lindau (VHL) tumor suppressor (a
negative regulator of HIF-1) promoter has a nuclear res-
piratory factor 1 (NRF-1, a nuclear transcription factor
associated with the expression of many genes required for
expression and function of the respiratory chain) recogni-
tion site. Since NRF-1 is a target for the PGC-1 family
coactivators, these proteins may promote mitochondrial
oxidative metabolism in part through the upregulation of
VHL expression.30
6 Tumor Biology
MYC regulates genes involved in glucose metabolism
by binding to and regulating virtually all glycolytic enzyme
genes as well as numerous genes involved in mitochon-
drial function.23 Deregulated MYC expression is a hall-
mark of a large fraction of all human tumors acting as an
oncogene in approximately 30% of all human cancers.32
Concerning mitochondria, MYC regulates the expression
of over 400 mitochondrial genes, including mitochondrial
transcription factor A (TFAM), an mtDNA transcription
and maintenance factor, as well as PGC-1α and PGC-1β.33
Therefore, gain/loss of MYC increases/reduces mitochon-
drial mass, respectively. In cancer, oncogenic MYC
increases cellular biosynthetic and respiratory capacity by
upregulating mitochondrial metabolism to support rapid
cell proliferation and by regulating the expression of pro-
teins that modulate mitochondrial dynamics.33,34
Other oncogenes commonly activated in cancers affect
metabolism, for example, activation of the phosphoi-
nositide 3-kinase (PI3K)-Akt-mTOR pathway can increase
cell size, glycolytic activity, metabolism, and cell sur-
vival.22 In this regard, recent data show that mTOR can act
as a major regulator of energy production in mitochon-
dria.35 mTOR regulates mitochondria at multiple levels;
transcriptionally, it regulates PGC-1α, ERR-α (a transcrip-
tion factor downstream of PGC-1α involved in the expres-
sion of components of the respiratory chain and control of
fatty acid oxidation), ERR-α target genes, and the expres-
sion of nuclear-encoded mitochondrial regulators such as
TFAM, mitochondrial ribosomal proteins, and compo-
nents of complex I and V.35 All these changes result in
increased mitochondrial biogenesis and oxidative phos-
phorylation. Translationally, mTOR regulates mitochon-
drial metabolism and biogenesis via repression of
inhibitory 4E-binding proteins (4E-BPs) that downregu-
late translation of nuclear-encoded mitochondrial proteins.
Finally, mTOR inhibits autophagy, a major catabolic pro-
cess in the cell that serves the cellular function of eliminat-
ing damaged mitochondria.33,35
RAS is an oncogene whose pathway is activated in a
variety of tumors, and its activation has been commonly
linked to alterations in glycolysis. In this regard, RAS
transformation, as well as increased mutant KRas copy
number, has been shown to induce metabolic changes in
immortalized cells characterized by increased expression
of glycolytic enzymes.36,37 Also, RAS transformation has
been shown to increase sensitivity to glucose depletion
since RAS-transformed cells were unable to upregulate
mitochondrial activity after glucose deprivation due to a
partially uncoupled mitochondrial respiration.36 In contrast,
increased mitochondrial activity has been linked to resist-
ance to therapy and recurrence in RAS-transformed can-
cers probably due to upregulation of PGC-1α.33 In BRAF
or NRAS mutant melanomas, resistance to mitogen-acti-
vated protein kinase (MAPK) inhibitors (which are acti-
vated by RAS transformation) was partially due to a switch
to oxidative metabolism mediated by PGC-1α upregulation
and was overcome by mTOR inhibition which repressed
PGC-1α expression.33 Also, in a mouse model of KRas-
mutant pancreatic ductal adenocarcinoma (PDAC), cells
that survive oncogene ablation showed increased PGC-1α
expression and mitochondrial function. Interestingly, the
reliance on mitochondrial respiration resulted in sensitivity
to oxidative phosphorylation inhibitors.38
Therefore, oncogenes commonly activated in cancer
not only activate glycolysis as Warburg initially proposed
but can also activate mitochondrial metabolism. Whether
this mitochondrial activation is particular to certain cells
within a tumor (those that are not in hypoxic regions where
HIF-1 is stimulated or to those cells which are resistant to
therapy) or whether this is a metabolic effect in tumor cells
with certain oncogenic mutations of specific cancer types
or tissues remains to be determined.
Of special interest to cancer cell metabolism is the fact
that p53, a crucial tumor suppressor, long recognized to
suppress cancer through the induction of cell-cycle-arrest
or apoptosis programs in response to a plethora of different
cellular stress signals, has been closely related to tumor cell
metabolism. These functions include the regulation of
metabolism, autophagy, and the oxidative status of the
cell.28 Concerning tumor cell metabolism, p53 can modu-
late the balance between glycolysis and oxidative phospho-
rylation. It can induce the expression of the protein synthesis
of cytochrome c oxidase 2 (SCO2) that is required for the
assembly of cytochrome c oxidase (COX).22 p53 mutation
in tumors causes downregulation of mitochondrial respira-
tion as a result of COX deficiency and a shift of cellular
metabolism toward glycolysis. Another target of p53 is
TP53-induced glycolysis and apoptosis regulator (TIGAR),
which decreases fructose-2,6-bisphospate levels in cells,
resulting in the inhibition of glycolysis, while stimulating
nicotinamide adenine dinucleotide phosphate (NADPH)
generation through the pentose-phosphate shunt.22 These
studies suggest that p53 is an important regulator of tumor
cell metabolism and that cells with wild-type p53 and cells
with mutations or deletions in this gene probably have dif-
ferences in glycolytic and mitochondrial metabolism.
Importantly, more than half of human cancers of a wide
variety of types harbor p53 mutations and even more have
alterations in the pathways that regulate p53 stability within
the cell.28 Importantly, p53 has an important relationship
with HIF-1, and the amplification of HIF-1-dependent
responses to hypoxia via the loss of p53 function contrib-
utes to the angiogenic switch, promoting cancer progres-
sion.39 Since HIF-1 can downregulate mitochondrial
activity; those tumors with HIF-1 activation and p53 muta-
tions or deletions could be the ones showing a dramatic
increase in glycolysis as well as an impaired mitochondrial
metabolism. In other tumors, the series of mutations driv-
ing tumorigenesis could have a specific effect on tumor cell
metabolism.
Maycotte et al. 7
Mitochondrial dynamics and
cell death
Apoptosis is triggered in response to various types of stress
that cancer cells experience during tumorigenesis such as
high levels of oncogene signaling, DNA damage associated
with hyper proliferation, or anti-cancer therapy. Also, apop-
tosis has been shown to be attenuated in tumors, and a
resistance to cell death has been listed as one of the hall-
marks of cancer cells.40 Mitochondria are a focal point of
apoptotic signaling. Diverse death stimuli ranging from
DNA damage to metabolic stress due to immune cell-­
mediated receptor ligation converge on mitochondria to
trigger the release of cytochrome c and other death-promot-
ing proteins from the IMS. The release of cytochrome c is
considered a critical decision point in apoptosis and occurs
through mitochondrial outer membrane permeabilization
(MOMP), which is regulated by the B-cell lymphoma 2
(BCL2) protein family members,41 and alterations in the
intrinsic or mitochondrial apoptotic pathway have been
implicated as a barrier to anti-cancer therapy.40
The BCL2 family of proteins is divided into pro- and
anti-apoptotic members, and they all share combinations
of BCL2 homology (BH) domains. BCL2-like proteins
(BCL-XL, BCL-W, A1, and MCL-1) are pro-survival and
antagonize the pro-apoptotic members of the family
(BAX, BAK, and BCL2 related ovarian killer (BOK)),
which mediate mitochondrial apoptosis through permea-
bilization of the OMM, allowing efflux of apoptogenic
proteins.42 BH3-only proteins (BCL2-like 11 (BIM),
BCL2 associated agonist of cell death (BAD), BH3-
interacting domain death agonist (BID), p53 upregulated
modulator of apoptosis (PUMA), and NOXA) of the
BCL2 family share this BH3 interaction domain and
antagonize BCL2 like proteins. The regulation of interac-
tions between pro-apoptotic and anti-apoptotic members
of the BCL2 family of proteins determines whether a cell
lives or dies in response to a stimulus.42 Once in the cyto-
sol, cytochrome c induces the oligomerization of cas-
pase-9, apoptotic protease activating factor 1 (APAF-1),
and ATP to form the apoptosome that goes on to activate
the executioner caspases, caspase-3 and caspase-7. These
terminal caspases cleave various cellular substrates that
lead to cellular dismantling through apoptosis.41–43
Interestingly, highly glycolytic cells like neurons and can-
cer cells can be refractory to cytochrome c–induced cas-
pase activation. In these cells, glucose-stimulated
production of glutathione as a result of NADPH produc-
tion through the pentose-­phosphate pathway inactivated
cytochrome c by keeping it in its reduced state.41
The BCL2 family proteins also have important effects on
metabolism. For instance, phosphorylated BAD can pro-
mote hepatic glycolysis by activating glucokinase in
response to the fed state.44 Also, proteins from the BCL2
family have been shown to modulate the balance between
mitochondrial fission and fusion. In this regard, mitochon-
drial fission has been generally associated with apoptotic
cell death. In healthy cells (i.e. in the absence of apoptotic
stimuli), the combined deletion of BAK and BAX results in
reduced fusion. In this setting, non-activated BAX may pro-
mote fusion by altering MFN2 distribution, mobility, and/or
complex assembly.43,45 Also, SIMH, which leads to highly
elongated mitochondria, has been shown to delay BAX acti-
vation upon exposure of cells to apoptotic stimuli.43
During apoptosis, mitochondrial fission occurs as an
early event, occurring within the same time frame as acti-
vation of BAX and MOMP. In this regard, diverse interac-
tions have been described for DRP1 and pro-apoptotic
BCL2 family proteins. In apoptotic cells with activated
BAX (recruited to the mitochondrial membrane), DRP1,
which normally cycles between the cytosol and the mito-
chondrial membrane, stably associates with the OMM due
to BAX/BAK dependent SUMOylation and precedes
MOMP.46 Also, DRP1 binds and is required for BAX mito-
chondrial translocation after an apoptotic stimulus.47 The
constricting ability of DRP1 may contribute to the mito-
chondrial membrane curvature required for the efficient
insertion of BAX and mitochondrial cristae remodeling,
suggesting a pro-apoptotic role for DRP1. Interference
with DRP1 function during apoptosis results in a block of
mitochondrial fission, leading to long interconnected orga-
nelles as well as a delay in cell death.46 In this study, the
authors suggest that during apoptosis, cycling of DRP1
between the cytoplasm and the mitochondria mediates
mitochondrial fission, whereas BAX/BAK dependent
membrane-associated DRP1 is involved in the subsequent
apoptotic events, such as the remodeling of the mitochon-
drial membrane that leads to MOMP and a loss of mem-
brane potential. Interestingly, DRP1 functions in apoptosis
could be independent of or complementary to mitochon-
drial fission, since DRP1-induced mitochondrial fragmen-
tation by itself is not sufficient to induce apoptosis.46,47
It has also been suggested that hyperfragmented mito-
chondria are not involved in apoptosis and that MFN1
establishes a mitochondrial size (fragmented, but not
hyperfragmented) that is permissive for pro-apoptotic
BCL2 family function.48 In this study, cells with hyper-
fragmented mitochondria (less than 0.5 µm) failed to sup-
port BAX-dependent membrane association and
permeabilization due to an inability to stabilize BAX–
membrane interactions. Bioenergetics of large and small
mitochondria were similar but only larger mitochondria
supported BAX integration to the OMM and mitochon-
drial pore formation. The authors suggest that while mito-
chondrial hyperfusion can protect from cell death, a
balanced, non–hyperfragmented mitochondrial network is
required for BAX-dependent MOMP after terminal ER
stress or chemotherapeutic drug treatment. In agreement
with the previous findings, increased sensitization to cispl-
atin- or paclitaxel-induced apoptosis was observed after
8 Tumor Biology
DRP1 inhibition with mitochondrial division inhibitor-1
(mDIVI-1), which induced mitochondrial fusion in the
human melanoma cell line A375, which normally displays
hyperfragmented mitochondria.48
Mitochondrial dynamics and cell cycle
progression
Mitochondria grow continuously throughout the cell cycle
and their dynamics and organization are tightly controlled
across its different phases to ensure proper cell division.49
In mammalian cells, evidence suggests that as cells pro-
gress through G1, mitochondrial membrane potential and
respiration markedly increase.50 Then, at G1/S, mitochon-
dria undergo a marked alteration in morphology, forming a
giant and tubular network with hyperpolarized and highly
coupled mitochondria.49,50 This network is associated with
increased energy production to prepare for DNA synthesis.
At this stage, mitochondrial hyperfusion also facilitates the
mixing of mitochondrial contents to promote their homoge-
neity within the cell, ensuring proper mitochondrial inherit-
ance following cellular division. Mitochondrial hyperfusion
triggers S-phase initiation and this alone is sufficient to
drive G0 quiescent cells into S phase of the cell cycle.49
During the following S, G2, and M phases, mitochon-
dria become increasingly fragmented, reaching the highest
fragmentation at mitosis to assure equal segregation of
mitochondrial contents between daughter cells.49 Mitotic
mitochondrial fission is directly regulated by kinases
involved in mitosis, like Aurora A kinase that promotes
RalA relocalization to mitochondrial membranes and
recruits the effector RalBP1. RalBP1 functions as a scaf-
fold for cyclin B/cyclin-dependent kinase 1 (cdk1) that
promotes phosphorylation of DRP1 at Ser616 resulting in
mitochondrial fission. Sustained mitochondrial hyperfu-
sion beyond the G1/S border induces replication stress
causing ATM-dependent G2/M delay and chromosomal
instability during mitosis. Also, prolonged mitochondrial
fusion causes mitochondrial bridges between daughter
cells resulting in a defective cytokinesis, unequal distribu-
tion of mitochondria, incorrect segregation of chromo-
somes, and aneuploidy. Cells that experience persistent
mitochondrial hyperfusion during mitosis present genomic
instability characterized by the presence of micronuclei
and disorganized nuclear structure.49
Mitochondrial dynamics and cancer
Cancer is a disease characterized by inappropriate cell pro-
liferation, dysregulated cell cycle control, and defects in
apoptosis. Since mitochondrial dynamics has been shown
to be involved in the aforementioned mechanisms, it is not
surprising to find recent evidence that strongly relate the
processes of mitochondrial fusion and fission to cancer
progression in diverse types of cancer.
As in normal cells, mitochondrial dynamics in cancer
cells have important implications for cellular function as
well as for sustaining proliferation and resistance to diverse
types of stress. In general, the majority of studies that have
explored mitochondrial morphology in tumor cells support
a pro-tumorigenic role for mitochondrial fission (Table 1).51
Reduced cancer cell growth and/or spontaneous apoptosis
induced by DRP1 inhibition alone or in combination with
chemotherapy have been observed both in vitro and in
vivo in several cancer types, including breast, colon, lung,
pancreatic, hepatocellular carcinoma, and melanoma.49,52–58
Moreover, alterations in the levels of proteins regulating
mitochondrial dynamics have been suggested as potential
biomarkers of malignancy or as a target for therapy in
diverse tumor types (Table 2). In this regard, inhibition of
mitochondrial fragmentation by silencing of DRP1 has
been associated with increased genomic instability49 and
reduced migration and invasion59 in breast cancer cell lines
which normally have a high level of fragmented mitochon-
dria. The mechanism underlying cellular dysfunction and
cell death induced by decreased mitochondrial fission
seems to be the replicative stress and mitotic defects that
severely affect the genomic integrity of cancer cells.
Impaired mitochondrial fission also causes mitochondrial
dysfunction characterized by accumulation of mtDNA
mutations and generation of ROS. This combined effect of
genome instability and mitochondrial dysfunction may
eventually result in the activation of the mitochondrial
apoptotic pathway, suggesting that inhibition of mitochon-
drial fission could be a potential mechanism to enhance
cancer cell apoptosis, to increase sensitivity to therapy, or
to potentially circumvent resistance of cancer cells to con-
ventional chemotherapy.49,60
In agreement with the previous observations, it has also
been reported that several cancer cell lines or cells that have
been transformed with oncogenes have more fragmented
mitochondria than their non-transformed controls.48,55,56,59
At least one of the molecular mechanisms involved in the
maintenance of fragmented mitochondria in cancer cells
has been recently elucidated and it has been proposed to
involve the MAPK signaling pathway, a proliferation path-
way activated in a variety of tumors. In normal cells, the
RAS-RAF-MEK-ERK (MAPK) pathway is activated by
growth factors and hormone signaling and its precise regu-
lation controls proliferation and cell death. In cancer cells,
excess signaling by growth factors, hormones, or onco-
genic mutations (like RASG12V or BRAFV600E) activate this
pathway which results in aberrant signaling, uncontrolled
proliferation, and silencing of the cell death machinery. A
hallmark feature of cancer cells with MAPK oncogenic
activation is an increase in anaerobic glycolysis (Warburg
effect) and glutaminolysis. More recently, mitochondrial
defects characterized by mitochondrial fragmentation with
decreased mitochondrial oxygen consumption rate and
mitochondrial ATP production have been described in
Maycotte et al. 9
RAS-transformed cells.55 While the RalGEF pathway has
been shown to promote mitochondrial fission during mito-
sis through DRP1 phosphorylation by Cdk1, RAS-
transformed cells and tumors show mitochondrial
fragmentation independent of the cell cycle, and this con-
stitutive mitochondrial fission has been attributed to the
activation of ERK2.55,56 DRP1 has been shown to be phos-
phorylated by ERK2 on Ser616, and this phosphorylation is
required for mitochondrial fission and tumor growth in
RAS-transformed tumors, emphasizing the need for MAPK
activation and consequent mitochondrial fragmentation in
tumors expressing oncogenic RAS.56 Interestingly, RAS is
mutated in up to 30% of all tumors and in 90% of PDACs,
and BRAFV600E mutations have been identified in approxi-
mately 66% of melanomas and in a smaller percentage in
other tumors (thyroid, colon, ovarian cancer, and sarco-
mas).61 Tumors or cell lines from these types of cancer are
known to have an altered metabolism and increased mito-
chondrial fragmentation55,56. Besides, DRP1 knockdown,
expression of the dominant-negative DRP1-K38A or inhi-
bition of DRP1 phosphorylation on Ser616 decreased tumor
growth in a RAS-driven mouse tumor model, suggesting
that DRP1 is a potential therapeutic target in tumors
expressing oncogenic RAS. Also, DRP1S616 phosphoryla-
tion was found to correlate with BRAFV600E in human mel-
anoma samples,55 and DRP1 phosphorylation or RAS
transformation led to decreased mitochondrial membrane
potential, increased production of mitochondrial ROS, and
reduced basal and maximal oxygen consumption rates,55
indicating that ERK2-mediated DRP1 phosphorylation is
responsible for decreased mitochondrial function in RAS-
transformed cells. In mouse tumors, DRP1 inhibition
induced a decrease in tumor vasculature and decreased vas-
cular endothelial growth factor (VEGF) messenger RNA
(mRNA).56 The authors suggest that one of the possible
mechanisms of tumorigenesis induced by MAPK-mediated
mitochondrial fission could be the activation of proangio-
genic signaling pathways, which are sensitive to mitochon-
dria-derived ROS. Also, with regard to MAPK-induced
mitochondrial fragmentation, c-Jun N-terminal protein
kinase (JNK) activation during chemotherapy-induced
apoptosis has been related to proteasomal degradation of
MFN2 through the activation of Huwe1 ubiquitin ligase,
decreasing mitochondrial fusion and inducing apoptosis.13
Therefore, MAPK activation in cancer has been linked to
mitochondrial fission and can induce transformation in
some cases (RAS transformation) and apoptosis in other
contexts (chemotherapy-induced apoptosis). Importantly,
in the first case, DRP1 inhibition (inhibition of fission)
decreased tumor growth in a mouse model and in patient-
derived pancreatic cancer cell lines;56 while in the second
case, MFN2 knockdown (inhibition of fusion) increased
apoptosis in doxorubicin-treated cells, highlighting the
need to precisely understand how to manipulate mitochon-
drial dynamics for cancer therapy.
MYC is another oncogene whose effects seem to be
mediated by the regulation of mitochondrial dynamics, and
in contrast to RAS, MYC has been suggested to induce
mitochondrial fusion.32,34 Graves et al.34 reported augmented
mitochondrial mass with increased membrane polarization, a
correction of OXPHOS deficiency, and mitochondrial fusion
upon Myc re-expression in myc−/− fibroblasts. Myc re-­
expression altered the levels of proteins involved in mito-
chondrial dynamics ultimately favoring fusion and
increasing mitochondrial mass.34 Also, in a recent study,
MYC induced PLD6 (a phospholipase of the OMM) expres-
sion and mitochondrial fusion to promote biosynthesis of
metabolic precursors and MYC-driven cell growth.32 Since
MYC potently stimulates cell growth and proliferation, the
authors suggest that MYC-induced mitochondrial fusion is
responsible for increased lipid, nucleotide, and protein
metabolism, which strain cellular energetic resources and
hence activate adenosine monophosphate–activated protein
kinase (AMPK, which is activated in response to high AMP
and low ATP levels) to inhibit yes-associated protein (YAP)/
TAZ coactivator activity. In this work, induction of mito-
chondrial fusion by mDIVI-1 was sufficient to activate
AMPK indicating that MYC exerts at least some of its
effects on metabolism and cell proliferation by inducing
mitochondrial fusion.32 Interestingly, MYC has been found
to be highly expressed in triple-negative breast tumors and
has been associated with poor prognosis in breast cancer
patients,32 suggesting a potential use for inhibitors of mito-
chondrial fusion for this type of cancer.
Regarding metastasis, human breast carcinomas and
metastasis to lymph nodes have been found to have higher
levels of DRP1 than ductal carcinoma in situ samples or
than the normal/adjacent tissue.59 Also, invasive breast
cancer cell lines have been found to have fragmented mito-
chondria, higher DRP1 and DRP1S616 levels, as well as
lower MFN1 than a non-metastatic cell line.59 In the same
study, DRP1 knockdown, DRP1 inhibition with mDIVI-1,
or MFN-1/2 expression decreased migration and invasion
in the metastatic cell lines without affecting cell cycle or
viability. Mitochondrial fission induced cell spreading
and increased lamellipodia formation as well as mito-
chondrial distribution to the lamellipodia region at the
leading edge of invading cells in response to chemoat-
tractants, suggesting a crucial role of mitochondrial fis-
sion in the migration and invasion of breast cancer cells.59
Also, since hypoxia is a major stimulator of migration and
invasion in cancer cells, another study found that hypoxia
increased the expression of DRP1 and mitochondrial fis-
sion in a glioblastoma cell line. In the same study, hypoxia-
induced migration was decreased with mDIVI-1 treatment
or a dominant-negative DRP1-K38A.62 These studies sug-
gest that targeting mitochondrial fission is likely to have a
therapeutic benefit in highly invasive cancers like glio-
blastoma, which is one of the most aggressive cerebral
gliomas, or in other highly metastatic cancers.
10 Tumor Biology
Other studies have found that tumor cells with increased
mitochondrial fragmentation are more sensitive to meta-
bolic stress and have proposed mitochondrial inhibition as
a therapeutic target in these types of cancers. For example,
in prostate cancer, androgens and androgen receptors play
critical roles in the proliferation of prostate cancer through
transcriptional regulation of target genes. Androgens have
been found to upregulate the expression of DRP1, facilitat-
ing mitochondrial fragmentation and apoptosis in prostate
cancer cell lines in response to mitochondrial stress.
Interestingly, in the same study, clinical tissue samples of
prostate carcinoma showed high levels of DRP1 in andro-
gen-dependent cancers but not in androgen independent
cancers. The authors suggest that androgens might func-
tion as a pro-apoptotic stimulus when combined with
agents that affect mitochondrial function in androgen-
dependent cancers.63 Also, with regard to hormonal regu-
lation of mitochondrial dynamics, estradiol treatment has
been shown to affect the levels of proteins regulating mito-
chondrial dynamics and to induce mitochondrial fusion in
the MCF-7, estrogen receptor positive cell line.64 The
above-mentioned studies indicate that hormones have a
strong influence on mitochondrial dynamics and the over-
all effect might involve hormone-specific effects, the type
of malignancy, or the type of hormone receptors present in
the cancer cell or tumor tissue,65 underscoring the impor-
tance of understanding how to manipulate mitochondrial
dynamics for the treatment of hormone-related malignan-
cies. Besides decreasing mitochondrial metabolism, it has
also been shown that mitochondrial fragmentation
increases glycolytic metabolism and makes cancer cells
more sensitive to glycolysis inhibitors.66 In this study, sur-
vivin, a member of the Inhibitor of Apoptosis Protein fam-
ily which is overexpressed in neuroblastoma, induced
increased DRP1 levels and mitochondrial fragmentation in
a neuroblastoma cell line. Mitochondrial fission increased
glycolysis and lactate production and made cells more sen-
sitive to 2-deoxyglucose alone or in combination with
chemotherapy. These studies suggest that mitochondrial
fragmentation could be a biomarker for treatment with
either or both mitochondrial and glycolytic metabolic
inhibitors.
It has also been suggested that mitochondrial inhibi-
tion could be a potential therapeutic target for the highly
tumorigenic tumor-initiating cells (TICs). TICs or cancer
stem cells have been defined as cells within the tumor
that possess clonal long-term repopulation and self-
renewal capacity. These cells have been proposed to be
responsible for therapy failure and the formation of
metastasis.67,68 In a PDAC model, dormant tumor cells
surviving oncogene-ablation (KRAS withdrawal) were
responsible for tumor relapse and had TIC features.
These TICs showed prominent expression of genes gov-
erning electron transport chain, autophagy, lysosome
activity, mitochondrial and peroxisomal oxidation,
increased PGC-1-α and mitochondrial mass, increased
oxygen consumption rate as well as a strong reliance on
mitochondrial respiration for survival, and a decreased
dependence on glycolysis for cellular energetics.38 In the
same study, mitochondria from TICs had an altered mor-
phology, were hyperpolarized, and produced more ROS.
The authors suggest that altered metabolic and mito-
chondrial functions are critical features of TICs in this
model, making them more resistant to apoptosis.
Interestingly, OXPHOS inhibition by oligomycin
decreased ATP content and induced cell death in TICs,
which were unable to upregulate glycolysis when com-
pared to KRAS expressing cells from the same model.
Altered metabolism in these TICs was attributed to
increased protein and fatty acid metabolism, making
them more sensitive to autophagy (which mediates lipid
droplet degradation) and β-oxidation inhibitors. These
findings indicate that TICs are more dependent on mito-
chondrial respiration than the highly glycolytic bulk of
tumor cells.38
In agreement with the previous report, in a different
model, brain TICs isolated from tumor xenografts or from
primary tumors have been found to have fragmented
mitochondria and increased levels of activating DRP1S616
phosphorylation relative to non-TICs, which showed
higher levels of DRP1S637 inactivating phosphorylation.
Interestingly, transfection with a phosphomimetic,
­inactivation-incompetent double-mutant DRP1S616E,    S637A
induced expression of stem cell markers in non-TIC tumor
cells, and DRP1 knockdown or its pharmacological inhibi-
tion with mDIVI-1 decreased tumor growth in two brain
tumor mouse models. Furthermore, while total DRP1 lev-
els were similar in normal and neoplastic brain tissues,
activating phosphorylation of DRP1 (DRP1S616) was
increased in glioblastomas, and a strong inverse correla-
tion was found between DRP1S616 and poor survival in
glioblastoma patients.69 In this work, the authors suggest
that cyclin-dependent kinase 5 (CDK5) was responsible
for DRP1 activation in brain TICs and that calcium-/calm-
odulin-dependent protein kinase type 2 (CAMK2) was
responsible for inhibitory phosphorylation of DRP1 in
Ser637 in non-TICs.69 Since glioblastomas rank among the
most lethal cancers, it will be interesting to explore DRP1
inhibition as a therapeutic strategy for these tumors.
In addition, mammospheres of breast cancer cell lines,
which are known to enrich TICs, as well as breast cancer
tumors, overexpress mitochondrial enzymes, proteins
involved in mitochondrial biogenesis, and protein inhibitors
of mitophagy when compared to their surrounding tissue.70
The previous findings suggest that tumor cells, and more
specifically TICs, resist stress by increasing their ATP pro-
duction through oxidative mitochondrial metabolism.
Regarding mitochondrial dynamics, MYC-induced prolif-
eration was shown to be mediated by the induction of
PLD6-mediated mitochondrial fusion and resulted in a
Maycotte et al. 11
decrease in mammosphere forming ability in CD44high/
CD24low mammary epithelial cells.32 This work, together
with the previously mentioned studies, suggests a relation-
ship between mitochondrial fragmentation and TIC fea-
tures or between mitochondrial fusion and a decrease in
TIC characteristics.
Other studies suggest that mitochondrial fusion could
be involved in resistance to therapy. Cervical and ovarian
cancer cell lines resistant to cisplatin showed a higher pro-
portion of tubular mitochondria and reduced sensitivity to
cisplatin-induced mitochondrial fragmentation and apop-
tosis induction than their non-resistant controls. In this
work, the authors show that p53 re-expression induces
mitochondrial fragmentation in p53 mut or p53 null cell
lines. The mechanism by which p53 regulates apoptosis in
cisplatin-sensitive cells involves cisplatin-mediated p53
phosphorylation which translocates to the mitochondria
and binds prohibitin1, releasing OPA1 and allowing its
processing to S-OPA1 by Oma1, whose proteolytic activa-
tion is also induced by p53, inducing mitochondrial frag-
mentation and apoptosis.10 This will be an interesting
hypothesis since, as we mentioned previously, more than
half of human cancers harbor p53 mutations and even
more have alterations in the pathways that regulate its sta-
bility within the cell,28 suggesting that the induction of
mitochondrial fragmentation could help restore the sensi-
bility to therapy.
Other links have been described between the mitochon-
drial fusion–fission machinery and p53. p53 has been
shown to bind DRP1, which mediates the monoubiquitina-
tion of p53 by mouse double minute 2 homolog (MDM2).
This allows p53 to translocate to the mitochondria and ini-
tiate necrosis in response to oxidative stress. Also, p53
directly promotes DRP1 expression in conditions of oxida-
tive stress, which induces mitochondrial fission and the
activation of caspase-3, and the enforced expression of
miR-30 attenuated mitochondrial fission by repressing
p53.71 Since p53 also transcriptionally regulates the
expression of proteins that promote mitochondrial apopto-
sis, it will be interesting to determine whether its role in
the induction of mitochondrial fragmentation causes cell
death by itself or if it is only a mechanism to facilitate cell
dismissal during apoptosis.
Discussion
Since changes in mitochondrial morphology are closely
linked to important cellular functions, including those
altered in cancer, it is not surprising that alterations in
mitochondrial dynamics are associated with tumor pro-
gression or resistance to therapy. Several alterations in
mitochondrial mass and ultrastructure have been reported in
neoplastic tissues, including ultrastructural heterogeneity,
cristal disorganization, altered mitochondrial membranes,
matricial vacuoles, mitochondrial swelling, and distorted
shapes,72 suggesting alterations in function when com-
pared to normal cells, but the functional implications of
these observations or their importance for cancer treatment
are not clear. Moreover, despite an increased understand-
ing of the molecular mechanisms regulating mitochondrial
fusion and fission and their role in certain cancer types or
cancer-related situations, a precise understanding of a
mechanism to manipulate mitochondrial dynamics is not
being used for cancer therapy.
The main complication for effectively targeting mito-
chondrial fusion or fission for therapy or for using mito-
chondrial morphology as a cancer biomarker is the
context-dependent role of mitochondria in diverse types of
cancer or settings (Table 1). However, with a few excep-
tions, most of the evidence suggests that increased mito-
chondrial fragmentation can be used as a diagnostic
biomarker for tumor progression or for certain oncogene
mutations (Table 2), although whether this is a general fea-
ture for all tumor types remains to be determined.
Oncogene transformation has been shown to have
diverse effects on mitochondrial morphologies: while
RAS transformation was shown to mediate mitochondrial
fragmentation,55,56 MYC-induced oncogenesis induced
mitochondrial elongation.32,34 Importantly, these changes
in mitochondrial dynamics were shown to be relevant for
oncogene-mediated transformation and proliferation.
Besides, p53, the most frequently mutated tumor suppres-
sor gene, induced mitochondrial fragmentation and apop-
tosis when re-expressed in p53-mutated or null ovarian
cancer cell lines.10 The aforementioned evidence suggests
that the array of mutations in oncogenes or tumor suppres-
sors could define mitochondrial morphology and probably
mitochondrial function within a particular tumor. In this
regard, steroid hormones were also shown to affect mito-
chondrial dynamics in hormone-related malignancies:
while androgens increased mitochondrial fragmentation in
androgen-sensitive prostate cancer, estradiol induced
mitochondrial fusion in an estrogen receptor–positive
breast cancer cell line. Thus, it will be important to identify
whether changes in mitochondrial morphology are specific
to an array of cancer mutations or to cancer cells in a tis-
sue, whether these changes contribute to tumor progres-
sion, and whether mitochondrial dynamics can be
effectively targeted for therapy.
Regarding treatment, the induction of mitochondrial
fragmentation is generally associated with a pro-apoptotic
effect in cancer cells treated with chemotherapy or ultravio-
let (UV) radiation, suggesting that the induction of fission
or inhibition of fusion could be potentially used in combi-
nation with other therapies during cancer treatment in sev-
eral malignancies. However, the proposal that mitochondria
need a minimal size permissive for apoptosis and that
hyperfragmented mitochondria are not involved in apopto-
sis48 raises important questions as to how to induce mito-
chondrial fragmentation and to what extent. Importantly, in
12 Tumor Biology

Table 1.  Mitochondrial dynamics and its relationship with cancer-related processes.

Mitochondrial Cancer-related Observation Treatment Cancer cell line Ref.

process process
Fission Pro-apoptotic DRP1 associates with OMM Staurosporine HeLa cervical cancer Wasiak et al.46
due to BAX/BAK dependent or anti-Fas- cell line
SUMOylation and precedes treated HeLa
MOMP. cells
Fission Pro-apoptotic DRP1-induced mitochondrial Staurosporine, HeLa and DLBCL Wasiak et al.46
membrane curvature is required anti-Fas, and UV (diffuse large B-cell and Wang
for efficient insertion of BAX. irradiation lymphoma) cell lines et al.47
Fission Pro-apoptotic JNK induced MFN2 proteasomal Doxorubicin U2OS osteosarcoma Leboucher
degradation decreasing cell line Guillaume
mitochondrial fusion during et al.13
chemotherapy-induced apoptosis.
Fission Pro-apoptotic Cisplatin resistant cervical and Cisplatin Cervical (OV2008 and Kong et al.10
ovarian cancer cell lines have more C13*) and ovarian
tubular mitochondria. P53 re- (A2780, SKOV3, and
expression in p53 mutant or null HEY) cancer cell lines
cell lines induced mitochondrial
fragmentation and apoptosis.
Fission Apoptosis DRP1-induced changes in – DLBCL cell lines Wang et al.47
mitochondrial fragmentation are
not sufficient to induce apoptosis.
Fission Apoptosis Hyperfragmented mitochondria Terminal Mfn1−/− MEFs and Renault et al.48
are not involved in apoptosis unfolded protein A375 human melanoma
but they need a minimal size response, cell line
permissive for pro-apoptotic BCL2 cisplatin, and
protein family function. paclitaxel
Fission Anti-apoptotic DRP1 inhibition sensitized to Cisplatin and A375 human melanoma Renault et al.48
treatment in a cancer cell line paclitaxel cell line
that normally displays fragmented
mitochondria.
Fission Pro- DRP1 knockdown induced – MDA-MB-231 breast Qian et al.49
tumorigenic genomic instability, cellular cancer cell line
dysfunction, and cell death in a
cancer cell line which normally
displays fragmented mitochondria.
Fission Pro- RAS-transformed cells have – E1A + RasG12V Serasinghe
tumorigenic fragmented mitochondria, and expressing MEFs, HEK- et al.55 and
inhibition of DRP1 decreased TtH HRASG12V, A375, Kashatus et al.56
tumor growth in a mouse model. or SK-MEL-28 BRAFV600E
cell lines, BT-474 ErbB2
overexpressing cell line,
and patient-derived
KRAS mutant pancreatic
cell lines
Fission Pro- Invasive breast cancer cell – MDA-MB-231 and Zhao et al.59
tumorigenic lines have more fragmented MDA-MB-436 breast
mitochondria, and DRP1 inhibition cancer cell lines
decreased migration and invasion
without affecting viability.
Fission Pro- Hypoxia-induced migration was Hypoxia (1% U251 glioblastoma cell Wan et al.62
tumorigenic decreased with mDIVI-1 treatment O2 or CoCl2 line
or expression of a dominant- treatment)
negative DRP1-K38A.
Fission Pro- Androgens increase DRP1 and Mitochondrial LNCaP and VCaP Choudhary
tumorigenic mitochondrial fragmentation stress prostate cancer cell line et al.63
in androgen-sensitive prostate
cancers, making them more
sensitive to mitochondrial stress.
(Continued)
Maycotte et al. 13

Table 1. (Continued)

Mitochondrial Cancer-related Observation Treatment Cancer cell line Ref.

process process
Fission Pro- Brain tumor–initiating cells – CD133+ brain tumor– Xie et al.69
tumorigenic, from tumor xenografts or initiating cells from
increased TIC primary tumors have fragmented tumors or xenografts
markers mitochondria and increased
DRP1S616. Phospho-mimetic
DRP1S616 induced TIC markers.
Fusion Increased MYC transformed cells have – MYC expressing von Eyss et al.32
proliferation increased mitochondrial fusion CD44high/CD24low
and decreased which promotes mitochondrial mammary epithelial cells
TIC features metabolism, cell proliferation and
decreases TIC markers.

UV: ultraviolet; TIC: tumor-initiating cells; OMM: outer mitochondrial membrane.

Some of the recent studies regarding mitochondrial fusion or fission and the suggested role in different aspects of apoptosis or cancer progression
are mentioned.

Table 2.  Alterations in proteins regulating mitochondrial dynamics in tumor samples and their suggested use as prognostic or
diagnostic biomarkers.

Alterations in Type of cancer Suggested use as a prognostic or diagnostic biomarker Ref.

proteins related to
mitochondrial dynamics
Increased DRP1 Lung Higher recurrence rate than patients with cytoplasmic DRP1. Nuclear Chiang
nuclear staining adenocarcinomas DRP1 was associated with advanced tumor stage, patient’s smoking et al.73
habits, and hypoxia. No difference in survival was found between
patients with high DRP1 levels and those with low DRP1 levels.
Increased DRP1 and Lung Increased DRP1 and decreased MFN2 staining was found in lung cancer Rehman
decreased MFN2 adenocarcinomas tissue when compared to healthy lung. This study used a small number et al.53
of tumor samples.
Increased p-DRP1S616 Melanoma Phosphorylation of DRP1 at Ser616 was significantly associated with Serasinghe
BRAFV600E mutations when compared to BRAFwt melanoma samples or et al.55 and
normal skin suggesting its use as a biomarker for BRAF mutations for Wieder
targeting MAPK or as a pharmacological target in this type of cancer. et al.74
Increased p-DRP1S616 Pancreatic ductal DRP1S616 correlated with ERK phosphorylation and mitochondrial Kashatus
adenocarcinoma fragmentation suggesting that mitochondrial fragmentation or DRP1S616 et al.56
could be used as a marker of MAPK pathway activation or as a marker
for targeting DRP1 in this type of cancer. This study used a small
number of tumor samples.
Increased DRP1 Breast cancer Increased DRP1 expression in breast cancer specimens when Zou et al.57
staining compared to adjacent normal tissues. Increased DRP1 staining in and Zhao
noninvasive ductal carcinoma in situ which was much more intense in et al.59
invasive carcinoma and metastases to lymph nodes.
Increased DRP1 Prostate cancer High DRP1 levels in post-surgery samples from prostate cancer Choudhary
staining patients correlated with the expression of the androgen receptor (AR) et al.63
suggesting a potential use for targeting mitochondria in AR+ prostate
cancers. This study used a small number of tumor samples.
Increased p-DRP1S616 Glioblastoma Increased DRP1S616 phosphorylation was increased in glioblastoma Xie et al.69
samples and correlated with worse patient survival.
Increased DRP1 Hepatocellular DRP1 mRNA was upregulated in hepatocellular carcinoma when Zhan et al.52
mRNA and protein carcinoma compared with non-tumor tissues. DRP1 protein levels were increased and Huang
and decreased MFN1 and MFN1 protein levels were decreased in tumor samples when et al.58
protein levels compared to peritumor area. Patients with high DRP1 expression had
a worse overall survival, while patients with high expression of MFN1
had a better overall survival. A lower ratio of DRP1/MFN1 was a
better predictor for better overall survival.

MAPK: mitogen-activated protein kinase; ERK: extracellular signal–regulated protein kinase; mRNA: messenger RNA.
14 Tumor Biology
cancer cells that normally display fragmented mitochondria,
DRP1 inhibition sensitized them to treatment10,48 or induced
cell death per se,49 underscoring the importance of under-
standing whether the induction of mitochondrial fragmenta-
tion or inhibition of fusion will only be useful to target
cancer cells with tubular mitochondria.
The suggestion that TICs, those cells within a tumor that
have tumor-initiating capacity and that have been sug-
gested to be responsible for tumor relapse, display increased
mitochondrial fragmentation and are more sensitive to
mitochondrial stress in several tissues (i.e. a pancreatic can-
cer model,38 breast cancer mammospheres,70 or brain tumor
TICs from tumor xenografts or primary tumors69) raises an
important suggestion for targeting mitochondria in combi-
nation with cancer therapy in order to eliminate TICs in the
tumor. Importantly, some of the above-mentioned studies
suggest targeting mitochondrial oxidative metabolism,38,70
and regarding mitochondrial dynamics, Xie et al.69 showed
that DRP1 knockdown or mDIVI-1 treatment decreased
brain TICs. Perhaps one of the most important findings of
this study is the fact that expression of DRP1 with two
mutations (Ser616E that mimics an activating phosphoryla-
tion and Ser637A that blocks inhibitory phosphorylation)
induced mitochondrial fragmentation and the expression of
some core stem cell regulators and repression of differen-
tiation markers in non-TICs. Therefore, mitochondrial
fragmentation by itself can induce TIC features in cancer,
making mitochondrial fission a potential target in these
malignancies. Whether this is particular for brain TICs or
whether it is a general feature of TICs in other tissues
remains to be established.
Finally, several questions remain to be answered. Are
there four mitochondrial states (hyperfused, fused, frag-
mented, and hyperfragmented) rather than just two (fused
and fragmented) and do they have different functions? Are
there particular biomarkers for each of these morpholo-
gies? How is this relevant to the different cancer cells? Is
mitochondrial fission only a feature of MAPK-transformed
cancers and fusion a feature of MYC transformation? How
do other oncogenes affect mitochondrial dynamics? How
does mitochondrial dynamics manipulation combine with
conventional chemotherapies used to treat these types of
cancer? Is mitochondrial inhibition useful for TICs in all
cancer types? Is mitochondrial fission necessary for migra-
tion in all cancer cells? It is very likely that a more precise
understanding of the mechanisms governing mitochon-
drial dynamics and their role in cancer will be available
soon, allowing for an improvement in cancer-related thera-
pies as well as for their use as cancer-related biomarkers.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
This work was supported by the following project from the
Instituto Mexicano del Seguro Social (IMSS):
CTFIS/1ORD/012/2011. P.M. is a recipient of a Cátedra
CONACYT (Consejo Nacional de Ciencia y Tecnología) for
young investigators (Cátedras CONACYT/3103).
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