Universidad de Chile

Facultad de Ciencias Veterinarias y Pecuarias

MITOCONDRIAS

Eduardo Kessi C.
Departamento de Ciencias Biológicas Animales
Facultad de Ciencias Veterinarias y Pecuarias
Universidad de Chile
ekessi@uchile.cl

EKC 2017 1
 Mitochondrion

Peroxisome

The major intracellular compartments of an animal cell. The cytosol (gray), endoplasmic reticulum,
Friedman JR & Nunnari J. 2014 Nature 503: 335-343
Golgi apparatus, nucleus, mitochondrion, endosome, lysosome, and peroxisome are distinct
compartments isolated from the rest of the cell by at least one selectively permeable membrane

Table 12 -1. Relative Volumes Occupied by the Major

Intracellular Compartments in a Liver Cell (Hepatocyte)

INTRACELLULAR PERCENTAGE OF TOTAL

COMPARTMENT CELL VOLUME

Cytosol 54
Mitochondria 22
Rough ER cisternae 9
Smooth ER cisternae plus 6
Golgi cisternae
Nucleus 6
Peroxisomes 1
Lysosomes 1
Endosomes 1

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 ATP sintasa Membrana externa
(F0F1) permeable a iones y
crestas moléculas pequeñas
Membrana interna
impermeable a la mayor parte de los
iones y moléculas pequeñas incluyendo H+.
Contiene:
*transportadores de
electrones (complejos I-IV)
*intercambiadores ATP-ADP
*ATP sintasa
*otros transportadores

Matriz
contiene:
*piruvato deshidrogenasa
*enzimas del ciclo de Krebs
*enzimas de la -oxidación de
ácidos grasos
*enzimas para oxidación de
aminoácidos
*DNA y ribosomas
ribosomas *ATP, ADP, Pi,
Mg2+, Ca2+, K+
y muchos intermediarios
porinas metabólicos

Approximate Lipid Compositions of Different Cell Membranes

PERCENTAGE OF TOTAL LIPID BY WEIGHT

LIPID LIVER CELL* RBC* MYELIN MIT** ER E. coli

Cholesterol 17 23 22 3 6 0
Phosphatidylethanolamine 7 18 15 25 17 70
Phosphatidylserine 4 7 9 2 5 trace
Phosphatidylcholine 24 17 10 39 40 0
Sphingomyelin 19 18 8 0 5 0
Glycolipids 7 3 28 trace trace 0
Others 22 13 8 21 27 30
* Plasma membranes; ** Inner and Outer membranes

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 P P

Structure of cardiolipin Cardiolipin is an unusual "double" phospholipid,

containing four fatty acid chains, that is found primarily in the inner
mitochondrial membrane.

What the Barth’s síndrome is?

Schematic of electron flow through the asymmetric CIII in the tight respirasome. Two electrons from NADH (top
right) are passed through CI (blue), reducing Q to QH2. Diffusing from the Q-tunnel, QH2 may enter the proximal Q
cavity of CIII (the oxidation cavity) or may diffuse into the membrane pool. QH2 passes one electron to cytochrome c
in the intermembrane space and one to Q in the distal cavity (the reduction cavity), creating the Q• intermediate.
Oxidation of a second QH2 in the proximal cavity will lead to reduction of Q• in the distal cavity to QH2, which can
then leave and join the membrane pool. Reduced cytochrome c can diffuse from CIII to CIV, probably through the
cytochrome c pool. The distal (from CI) cytochrome c reduction site in CIII is shown in a pale colour, as its operation
may be suboptimal due to the restricted movement of nearby UQCRFS1. Letts JA et al. 2016 Nature 537:644-648
Scheme showing how the loss of supercomplex organization may be involved in a vicious circle of oxidative stress and
energy failure. ROS production by Complex I is enhanced as a consequence of supercomplex disassembling. Membrane
phospholipid peroxidation and consequent further loss of supercomplex organisation may occur due to mitochondrial
oxidative stress, thus perpetuating the vicious circle. Depending on the amount produced, ROS can also operate as signalling
molecules from mitochondria to the cell. Genova ML & Lenaz G 2014 Biochim Biophys Acta 1837:427-443

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 Distribution of FoF1 ATP-synthase molecules identified in cryo-electron tomograms from isolated
mitochondrial cristae. Flies with genetic knockout of cardiolipin synthase (CLS) or tafazzin(TAZ) have
lower, more disorganized arrays of ATP-synthase molecules.
https://med.nyu.edu/skirball-lab/stokeslab/mito.html
The subcompartments of mitochondria and chloroplasts. In contrast to the
cristae of mitochondria (A), the thylakoids of chloroplasts (B) are not connected
to the inner membrane and therefore form a sealed compartment with a separate
internal space.

mitocondrias microtúbulos

The relationship between mitochondria and microtubules. (A) A light micrograph of

gota de grasa
chains of elongated mitochondria in a living mammalian cell in culture. The cell was miofibrilla
stained with a fluorescent dye (rhodamine 123) that specifically labels mitochondria in mitocondria
living cells. (B) An immunofluorescence micrograph of the same cell stained (after
fixation) with fluorescent antibodies that bind to microtubules. Note that the mitochondria
tend to be aligned along microtubules.

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 mitocondria

axonema flagelar
Morfología mitocondrial del cardiomiocito. A: microscopía electrónica de
cardiomiocito de rata neonata en cultivo (panel izquierdo) y tejido cardiaco de rata adulta
miofibrilla cola del espermatozoide (panel derecho); en el cardiomiocito neonato, las mitocondrias (M) se encuentran
músculo cardíaco
distribuidas en el citoplasma y alrededor del núcleo (N), mientras que en el corazón
adulto las mitocondrias se encuentran alineadas entre las unidades sarcoméricas (S).

Kuzmicic J. et al. 2011 Rev Esp Cardiol. 64(10)::916–923

Homogeneizado

Centrifugación a baja velocidad

1000g, 10 min
Sedimento contiene
células enteras
nucleos
citoesqueletos
Sobrenadante sometido a centrifugación a velocidad media
Fraccionamiento subcelular por centrifugación
diferencial. Centrifugaciones repetidas a
20000g, 20 min Sedimento contiene velocidades progresivamente mayores permiten
mitocondrias fraccionar homogeneizados de células en sus
lisosomas componentes. En general, los componentes más
peroxisomas
pequeños requieren de valores mayores de fuerza
Sobrenadante sometido a centrifugación a velocidad alta centrífuga para sedimentarlos.
80000g, 60 min
Sedimento contiene
microsomas
vesículas pequeñas
Sobrenadante sometido a centrifugación a velocidad muy alta

150000g, 180 min Sedimento contiene

ribosomas
virus
macromoléculas

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EKC 2017 7
 Tomography of an isolated rat-
liver mitochondrion. (a) Surface-
rendered 3D image of an isolated
rat-liver mitochondrion. C,
cristae; IM, inner boundary
membrane; OM, outer membrane.
Arrowheads point to tubular
regions of cristae that connect
them to IM and to each other.
Reproduced, with permission,
from Ref. 4. (b) Region of a 5-nm
slice from the same tomogram
showing numerous contact sites
between OM and IM. Arrow
Computer models generated from segmented 3D tomograms of a
points to particle bridging OM
mitochondrion in chick cerebellum. (a) The entire model showing all
with attached vesicle of putative
cristae in yellow, the inner boundary membrane in light blue, and the
endoplasmic reticulum. Bar, 0.4
outer membrane in dark blue. (b) Outer membrane, inner boundary
m.( TIBS 25:319, 2000)
membrane and four representative cristae in different colors. (TIBS
25:319, 2000)

Structure of a mitochondrion. (A) Tomographic slice through a three-dimensional map of a mouse

Role of oxidized cardiolipin in the release of cytochrome c from mitochondria. ROS
production causes cardiolipin oxidation which, in turn, promotes cytochrome c detachment from
the IMM. Cytochrome c is then released into the cytosol through OMM, via MPTP or Bax/Bak
oligomerization (for details see the text). OMM, outer mitocondrial membrane; IMM inner
mitochondrial membrane; ETC, electron transport chain; AAC, ADP/ATP carrier; CL, cardiolipin;
CLox, oxidized cardiolipin, Cyt c, cytochrome c.
Paradies G. et al. 2014 Biochimica et Biophysica Acta 1837: 408–417
heart mitochondrion determined by electron-microscope tomography. The outer membrane envelops the
inner boundary membrane. The inner membrane is highly folded into tubular or lamellar cristae, which
crisscross the matrix. The dense matrix, which contains most of the mitochondrial protein, appears dark
in the electron microscope, whereas the intermembrane space and the crista space appear light due to
their lower protein content. The inner boundary membrane follows the outer membrane closely at a
distance of ≈20 nm. The inner membrane turns sharply at the cristae junctions, where the cristae join the
inner boundary membrane. (B) Tomographic surface-rendered portion of a yeast mitochondrion,
showing how flattened cristae project into the matrix from the inner membrane. (C) Schematic drawing
of a mitochondrion showing the outer membrane (gray), and the inner membrane (yellow). Note that
the inner membrane is compartmentalized into the inner boundary membrane and the crista membrane.
There are three distinct spaces: the inner membrane space, the crista space, and the matrix.

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 Resumen del metabolismo energético
que ocurre en las mitocondrias. Los
ácidos grasos y el piruvato entran en la
mitocondria (parte superior de la figura)
y son transformados en acetil CoA. El
acetil CoA se metaboliza en el ciclo del
ácido cítrico (ciclo de Krebs). En el
proceso de la fosforilación oxidativa,
los electrones pasan a lo largo de la
cadena de transporte de electrones en
las crestas de la membrana interna
desde las coenzimas reducidas
producidas en el ciclo de Krebs hasta el
oxígeno (O2). Este transporte de
electrones genera una gradiente de
protones que impulsa la producción de
ATP por la ATP sintasa. Las membranas
que comprenden la membrana interna
mitocondrial -la membrana límite
interior y las de las crestas contienen
diferentes mezclas de proteínas por lo
que están sombreadas de manera
diferente en esta figura.

Plasticidad mitocondrial. La observación

de una mitocondria individual, al interior
de una célula viva durante un cierto período
de tiempo, permite constatar que ocurren
cambios rápidos en su morfología.

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 A dynamic mitochondrial reticulum. (A) In yeast cells, mitochondria form a
continuos reticulum underlying the plasma membrane. (B) A balance between
fission and fusion determines the arrangement of mitochondria in different
1 m cells. Time-lapse fluorescence microscopy shows the dynamic behaviour of
the mitochondrial network in a yeast cell. In addititon to shape changes,
fission and fusion constantly remodel the network (red arrows). The pictures
were taken at 3-minute intervals

Mitochondria, Stained Green, Form a Network Inside a

Fibroblast Cell. Mitochondria oxidize carbon fuels to form cellular
energy. This transformation requires electron transfer through
several large protein complexes some of which pump protons,
forming a proton gradient that powers the synthesis of ATP.

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 Staining of nuclear and mitochondrial
DNA. In this confocal micrograph of a
human fibroblast, the nuclear DNA is
stained with the dye DAPI (blue) and
mitochondrial DNA is visualized with
fluorescent antibodies that bind DNA
(green). The mitochondria are stained
with fluorescent antibodies that
recognize a specialized protein
translocase specific to the outer
mitochondrial membrane (red).

The organization and distribution of mitochondria and mtDNA in higher eukaryotes.

Mitochondrial organization is a conserved feature. a, mtDNA in a human fibroblast is packaged
within nucleoids (green) distributed within tubular mitochondria (red) around the nucleus (blue).
Scale bar, 20 microns. b, A similar distribution is seen in a yeast cell with nucleoids (green) within
mitochondria (red). Scale bar, 2 microns
Friedman JR & Nunnari J. 2014 Nature 503: 335-343

Fusión y fisión mitocondrial. Cardiomiocitos neonatos vivos tratados con la sonda

mitocondrial MitoTracker Green se observaron mediante microscopía confocal. La
fotografía central muestra la morfología mitocondrial en condición control; la transducción
del cardiomiocito con el adenovirus antisentido para la proteina mitofusina 2 (panel
izquierdo) produce fragmentación de la red mitocondrial por una disminución en los
procesos de fusión, mientras que la expresión adenoviral de una forma dominante negativa
de la proteína relacionada con la dinamina-1 –DRP1(panel derecho) produce fusión por
disminución de los procesos de fisión.
Kuzmicic J. et al. 2011 Rev Esp Cardiol. 64(10)::916–923
Mitochondrial fusion dissected. Fusion of mitochondria requires the sequential interaction of
outer and inner membranes. Fusion of the outer membranes of two adjacent mitochondria
requires low GTP levels, whereas the subsequent fusion of the inner membranes requires high
GTP levels and the presence of an inner-membrane electrical potential. (Box) Three components
of the mitochondrial fusion machinery are known: the outer-membrane GTPase (Fzo1), the
intermembrane-space GTPase (Mgm1), and the outer-membrane protein Ugo1 that links both
GTPases. Formation of Fzo1 homodimers between adjacent mitochondria promotes their initial
tethering. Subsequent fusion of the two mitochondria requires the cooperation of Fzo1, Ugo1,
Mgm1, and additional fusion proteins and regulatory factors. (Science 305:1723-1724, 2004)

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 Mitochondrial morphology is partly dependent on a proper balance between fusion and fission processes.
Mammalian mitochondrial fusion is mediated mainly by Mfn1, Mfn2, and Opa1. Reduction in the activity of these
proteins by repression or by the presence of loss-of-function mutants or ablation of these proteins causes
mitochondrial fragmentation or reduction in the extent of mitochondrial filaments. In contrast, reexpression of
Mfn1, Mfn2, or OPA1 in cells with prior deficient activity of these any of these proteins promotes the formation of Evolution of mitochondrial division site placement mechanisms.
mitochondrial filaments. Furthermore, gain-of-function of some of these proteins in the presence of abolished
mitochondrial fission results in long mitochondrial filaments. Mammalian mitochondrial fission is mediated by
Drp1, Fis1, and MTP18. Reduction in the activity of these proteins by repression or by mutation, or ablation of
these proteins causes elongation of mitochondrial network. In contrast, overexpression of these proteins causes
mitochondrial fragmentation. Liesa et al. 2009 Physiol Rev 89: 799–845 Friedman JR & Nunnari J. 2014 Nature 503: 335-343

Interaction of mitochondria with the

endoplasmic reticulum. (A) Fluorescence
light microscopy shows that tubules of the ER
(green) wrap around parts of the mitochondrial
network (red) in mammalian cells. The
mitochondria then divide at the contact sites.
After contact is established, fission occurs
within less than a minute, as indicated by time-
lapse microscopy. (B) Schematic drawing of an
ER tubule wrapped around part of the
mitochondrial reticulum. It is thought that ER–
mitochondrial contacts also mediate the
exchange of lipids between the two membrane
systems.
The cellular location of mitochondrial DNA replication. Using microscopy in living human cells,
Lewis et al.2 monitored replication of the DNA structures called nucleoids in mitochondria. a, The
authors observed that sites of DNA replication, identified from co-localization of nucleoids with
either mitochondrial DNA polymerase protein or a mitochondrial division enzyme, were located in
regions of the mitochondrion in close association with endoplasmic reticulum (ER) tubule
structures. b, When the authors manipulated the ER so that it was mainly in a sheet-like form
rather than in a tubular form, they observed a decrease in nucleoid replication.
Ziviani & Scorrano 2016 Nature 538:326-327

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 Biological functions of mitochondrial
dynamics. a | The mitochondrial life cycle
starts with growth and division of pre-existing
organelles (biogenesis) and ends with
degradation of impaired or surplus organelles
by mitophagy (turnover). In between,
mitochondria undergo frequent cycles of fusion
and fission that allow the cell to generate
multiple heterogeneous mitochondria or
interconnected mitochondrial networks,
depending on the physiological conditions. b |
Fusion and fission of mitochondria are
important for many biological functions. Division
is required for inheritance and partitioning of
Integration of mitochondrial stress response pathways and their coordination with mitochondrial shape..
organelles during cell division, for the release of
Mitochondria in healthy cells generate an electrochemical potential that serves in oxidative phosphorylation and
pro-apoptotic factors from the intermembrane
drives the import of proteins into the organelle. Damage that leads to a loss (blue) of mitochondrial membrane
space, for intracellular distribution by
potential can lead to a loss of protein import efficiency. In the (UPRmt) pathway, loss of import leads to the
cytoskeleton-mediated transport and for
accumulation of the transcription factor ATFS1 in the nucleus, activating a transcriptional mitochondrial repair and
turnover of damaged organelles by mitophagy.
metabolic adaptation response. Loss of membrane potential also triggers the OMA1-dependent proteolysis of long
Fused mitochondrial networks are important for
isoforms of the inner membrane fusion DRP OPA1, which attenuates mitochondrial fusion and potentially increases
the dissipation of metabolic energy through
ER-mediated mitochondrial division (ERMD), resulting in mitochondrial fragmentation. These fragmented
transmission of membrane potential along
mitochondria that have lost the ability to respire and import may also accumulate the PINK1 kinase, which triggers
mitochondrial filaments and for the
mitophagy. In addition, under these conditions, the ERMD domain may be altered to directly promote BAX
complementation of mitochondrial DNA
oligomerization on the mitochondrial outer membrane, outer-membrane permeabilization and cytochrome c release,
(mtDNA) gene products in heteroplasmic cells
leading to cell death. Mitochondrial dysfunction and stresses such as starvation can trigger mitochondrial hyperfusion,
to counteract decline of respiratory functions in
which is dependent on maintenance of mitochondrial membrane potential (red) and the presence of both long and
ageing (X and Y depict alleles of different
short OPA1 isoforms. Hyperfused mitochondria can transiently buffer the effects of respiratory chain dysfunction and
mitochondrial genes).
do not enter the mitophagy pathway.
Westermann B 2010 Nature Rev. Mol. Cell Biol. 11:873-884 Friedman JR & Nunnari J. 2014 Nature 503: 335-343

Quality control (QC) surveillance of mitochondria. Intraorganellar proteases exert QC
and regulatory functions to maintain respiratory chain (RC) activity. The functionality of
damaged mitochondria can be restored by fusion and content mixing within the
mitochondrial network. Severely damaged mitochondria fragment and are removed by
mitophagy or induce apoptosis by the release of pro-apoptotic proteins. (Tatsuta T. and T.
Langer 2008 EMBO Journal 27:306–314)
Quality control (QC) of mitochondrial proteins. ATPdependent proteases present in
various subcompartments of mitochondria recognize non-native polypeptides and
trigger their proteolysis to peptides that are further degraded by oligopeptidases. At the
same time, energy-dependent proteases can act as processing enzymes ensuring
assembly and integrity of RC. Recent evidence links the UPS to mitochondrial QC and
the regulation of mitochondrial dynamics. OM, outer membrane; IMS, intermembrane
space; IM, inner membrane; M, matrix.

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 Quality control of mitochondria by mitophagy. ROS produced by damaged
mitochondria induces mitochondrial fragmentation and mitochondrial permeability
transition (MPT). Damaged mitochondria are engulfed by autophagosomes selectively
and eliminated, preventing the release of pro-apoptotic proteins and apoptosis.

Dysfunction of mitochondria has severe cellular Mitochondria are dynamic organelles

consequences and is linked to ageing and
neurodegeneration in human. Several surveillance
whose morphologies are controlled by
strategies have evolved that limit mitochondrial damage fusion and fission. Mitochondrial fusion
and ensure cellular integrity.
and fission are essential for normal
Intraorganellar proteases conduct protein quality control mitochondrial function, implying that
and exert regulatory functions, membrane fusion and
fission allow mitochondrial content mixing within a cell,
mitochondria do not function well as
and the autophagic degradation of severely damaged autonomous organelles.
mitochondria protects against apoptosis.

Chan D.C. 2006 Annu. Rev. Cell. Dev. Biol. 22:79-99

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 Mitochondrial dynamics plays important
roles in vertebrate development and
programmed cell death. Mutations in the
mitochondrial fusion machinery lead to
two human neurodegenerative disorders,
Charcot-Marie-Tooth subtype 2A and
autosomal dominant optic atrophy.

Chan D.C. 2006 Annu. Rev. Cell. Dev. Biol. 22:79-99

Bacteria Archaea Eucarya

Animales

Hongos
Euryarcheota Plantas

Creanarcheota

Hipótesis endosimbiótica del origen de la mitocondria. Las ramificaciones más cercanas al

nodo original en el Arbol de la Vida separan a las bacterias de las arqueas y de los eucariotes.
Estos últimos evolucionaron a partir de un ancestro de tipo arquea. Se muestran tres etapas re-
levantes: (1) la evolución del citoesqueleto y del sistema de endomembranas, seleccionado por
la capacidad de “engullir” partículas sólidas de alimento como por ej. bacterias; (2) la conver- Filogenia universal determinada por análisis de secuencias de RNA
sión de una -proteobacteria no digerida en simbiontes respiratorios intracelulares (endosim- ribosomal (Woese C. PNAS 99: 8742-8747, 2002)
biontes) y (3) la pérdida de la mayoría de los genes de la -proteobacteria original y la trans-
ferencia de los otros hacia el núcleo.

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 bacteria Eucariote amitocondriado tipo I
membrana interna (MI)
citoplasma Orgánicos
membrana externa (ME)

mitocondria cloroplasto

Glucosa

Glicólisis
ATP

membrana interna Piruvato

membrana externa

Los sistemas de membrana de las bacterias, las mitocondrias y cloroplastos están Piruvato
filogenéticamente relacionados. Las mitocondrias y cloroplastos son organelos
originados a partir de bacterias y han conservado los mecanismos de conversión de energía
ATP
bacterianos. Al igual que sus antepasados bacterianos, mitocondrias y cloroplastos tienen
una externa y una membrana interna. Cada una de las membranas de colores en este
diagrama contiene cadenas de transporte de electrones. Las invaginaciones de la
membrana mitocondrial interna y el sistema de membrana interna del cloroplasto Anaeróbico CO2 OAc- CO2 EtOH
contienen la maquinaria para la respiración celular y la fotosíntesis, respectivamente.

Eucariote amitocondriado tipo II Eucariote mitocondriado

Orgánicos Orgánicos

Glucosa Glucosa

Glicólisis Glicólisis
ATP ATP
Hidrogenosoma Mitocondria
Piruvato Piruvato

Piruvato Piruvato
Oxígeno
ATP ATP Respiración
ATP ATP

Anaeróbico H2 EtOH CO2 H2O Aeróbico

CO2

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EKC 2017 17
 Metabolism in a eukaryotic cell. Glycolysis, the citric acid cycle, and oxidative
phosphorylation. Glycolysis takes place in the cytoplasm. Within the mitochondrion, the
citric acid cycle occurs in the mitochondrial matrix, and oxidative metabolism occurs at the
internal folded mitochondrial membranes (cristae).

alimentos

Etapa 1:
desdoblamiento de proteínas polisacáridos grasas
macromoléculas a Luz solar Alimentos
subunidades simples
monosacáridos ácidos grasos
aminoácidos
(ej. glucosa) y glicerol
glicolisis

Etapa 2:
desdoblamiento de ATP
las subunidades a
acetil-CoA y pro-
Esquema simplificado de los
piruvato
ducción de canti- tres estados del catabolismo Electrones de “alta energía”
dades limitadas de
ATP y NADH que transforman los alimentos
acetil-CoA
en productos de desecho. Estos Transporte Producción
conjuntos de reacciones activo de calor
ciclo de
Krebs producen ATP, el que es usado Gradiente electroquímico
transmembrana
Etapa 3: para impulsar reacciones (gradiente de protones)
oxidación completa
del acetil-Coa hasta biosintéticas y otros procesos
CO2 y H2O con pro-
ducción de grandes poder reductor
que requieren energía en las
Rotación del Potencial
cantidades de ATP y NADH células. flagelo en eléctrico
NADH fosforilación bacterias E
oxidativa
CR

ATP
O2
Síntesis Síntesis
NH3 H2O CO2 de ATP de NADPH

desechos

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 Glucosa

glicolisis
(10 reacciones sucesivas)

condiciones condiciones
anaeróbicas 2 Piruvato anaeróbicas
condiciones
aeróbicas
2 Etanol + 2CO2 2 Lactato
2CO2
fermentación fermentación a lactato
alcohólica en en músculo, eritrocitos,
2 Acetil CoA
levaduras otras células y
microrganismos
ciclo de
Krebs

4CO2 + 4H2O
Células animales, vegetales
y muchas bacterias bajo
condiciones aeróbicas

Ciclo de Krebs
(ciclo de los ácidos tricarboxílicos)
(ciclo del ácido cítrico)

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 Coupling of Phosphorylation to Electron and Hydrogen Transfer by
a Chemiosmotic Type of Mechanism
NADH + H+ NAD+
Peter Mitchell, University of Edinburgh, Edinburgh, Scotland

Procesos de transducción
de energía
Fosforilación oxidativa
In the exact sciences, cause and effect are no more than events
linked in sequence. Biochemists now generally accept the idea
that metabolism is the cause of membrane transport. The
underlying thesis of the hypothesis put forward here is that if
the processes that we call metabolism and transport represent
events in a sequence, not only can metabolism be the cause of
transport, but also transport can be the cause of metabolism.

ADP + Pi ATP + H2O

Nature, 1961, Volume 191, pages 144-148

MITOCONDRIA
Mitchell's Nobel Prize Lecture, in 1978, began as follows:
Although I had hoped that the chemiosmotic rationale of
vectorial metabolism and biological energy transfer might one Gradiente de protones
day come to be generally accepted, it would have been
presumptuous of me to expect it to happen. Was it not Max
NADH
Planck who remarked that a new scientific idea does not H+
triumph by convincing its opponents, but rather because its H+
opponents eventually die? The fact that what began as the e-
H+
chemiosmotic hypothesis has now been acclaimed as the O2
chemiosmotic theory has therefore both astonished and Ciclo
Azucares de
delighted me, particularly because those who were formerly my y grasas Krebs
most capable opponents are still in the prime of their scientific CO2 H2 O
lives.
Productos

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 NADH

Amital FMN NADH - Q

Rotenona deshidrogenasa
Piericidina A Fe-S
(Complejo I)

Succinato FAD Fe-S CoQ

Succinato deshidrogenasa Cit b

CoQ - Cit c
(Complejo II) Fe-S reductasa
Antimicina A
Cit c1
(Complejo III)

Cit c

Cianuro Cit a Cit c oxidasa

CO (Complejo IV)
Azida Cit a3

O2

A summary of the energy converting

metabolism in mitochondria. Pyruvate IMM
and fatty acids enter the mitochondrion
(top of the figure) and are broken down
to acetyl CoA. The acetyl CoA is
metabolized by the citric acid cycle,
which reduces NAD+ to NADH, which
then passes its high-energy electrons to IMM
the first complex in the electron-
transport chain. In the process of
oxidative phosphorylation, these
electrons pass along the electron
transport chain in the inner membrane
cristae to oxygen (O2). This electron
transport generates a proton gradient,
which drives the production of ATP by IMM
the ATP synthase. Electrons from the
oxidation of succinate, a reaction
intermediate in the citric acid cycle, take
a separate path to enter this electron-
transport chain. The membranes that
comprise the mitochondrial inner
membrane (the inner boundary Proposed models for the organization of oxidative phosphorylation complexes.
membrane and the crista membrane)
contain different mixtures of proteins
Proposed models for the organization of ETC complexes (I, II, III, IV and V), and AAC
and they are therefore shaded into supercomplexes. Each complex in the supercomplex organization is shown as
differently in this diagram. monomer. A, random collision model. B and C, supercomplex organization. Q, coenzyme
Q; C, cytochrome c; AAC, ADP/ATP carrier.; IMM Inner mitochondrial membrane.

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 Acute temperature Activation of
drop adrenergic neurons
inervating BAT cells
Activation of
 adenylyl ciclase

Phosphorylation of Activation of
CREB Protein kinase A

Phosphorylated CREB 1 in every 2000 electrons goes directly from NADH to

migrates to nucleus and
Induction of PGC-1 oxygen which results in production of superoxide anion
binds to CRE element in

.
Activates PPAR
the PGC-1 gene promoter
e- e- 2-
Induction of UCP1 O2 O2 O2
Heat production

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 Superoxide
. Dismutase (SOD)

2O2 + 2H+ O2 + H2O2

Superoxide Dismutase Mechanism. The oxidized Cit c
form of superoxide dismutase (Mox) reacts with one Espacio inter-
. membrana
superoxide ion to form O2 and generate the reduced
form of the enzyme (Mred). The reduced form then
reacts with a second superoxide and two protons to
form hydrogen peroxide and regenerate the oxidized
form of the enzyme. Fumarato
Succinato
Dismutation A reaction in which a single
reactant is converted into two different products.
Matriz mitocondrial

Potencial Sintesis de Potencial

Catalase químico ATP impulsada eléctrico
H2 O2 + H2 O2 O2 + 2H2O pH por la fuerza 
(alcalino protón-motriz (negativo
Glutathione dentro) dentro)
peroxidase
H2O2 + 2GSH GSSG + 2H2O

Otras funciones para las mitocondrias en el metabolismo celular. Las

mitocondrias no sólo producen ATP; existen muchos procesos críticamente
importantes (como los indicados en la figura) que enfatizan lo poco exacto que
resulta describir a la mitocondria únicamente como el organelo que oxida
piruvato y ácidos grasos para “alimentar” la fosforilación oxidativa

EKC 2017 23
 Schmidt et al. 2010 Nature Rev Mol Cell Biol. 11:655-667

Biogenesis of the respiratory- NÚCLEO CITOSOL

chain proteins in human DNA
mitochondria. Most of the protein genómico RNA RNA
components of the mitochondrial
-amanitina
respiratory chain are encoded by cicloheximida
nuclear DNA, with only a small
number encoded by mitochondrial proteína
precursora
DNA (mtDNA). Transcription of
mtDNA produces 13 mRNAs, all of
which encode subunits of the
oxidative phosphorylation system, MITOCONDRIA O proteína
and the 24 RNAs (22 transfer CLOROPLASTO importada
RNAs and 2 ribosomal RNAs) proteína fabricada
DNA RNA
needed for translation of these en el organelo
mRNAs on the mitochondrial acridinas Cloranfenicol
ribosomes (brown). o etidio eritromicina
tetraciclina

EKC 2017 24
EKC 2017 25

Protein import by mitochondria. The N-terminal signal sequence of the
mitochondrial precursor protein is recognized by receptors of the TOM complex. The
protein is then translocated through the TIM23 complex so that it transiently spans
both mitochondrial membranes. The signal sequence is cleaved off by asignal
peptidase in the matrix space to form the mature protein. The free signal sequence is
then rapidly degraded (not hown)
EKC 2017
The role of energy in protein import into the mitochondrial matrix space. (1)
Bound cytosolic hsp70 chaperone is released from the precursor protein in a step that
depends on ATP hydrolysis. After initial insertion of the signal sequence and of
adjacent portions of the polypeptide chain into the TOM complex translocation
channel, the signal sequence interacts with a TIM complex. (2) The signal sequence is
then translocated into the matrix space in a process that requires the energy in the
membrane potential across the inner membrane. (3) Mitochondrial hsp70, which is part
of an import ATPase complex, binds to regions of the polypeptide chain as they become
exposed in the matrix space, pulling the protein through the translocation channel,
using the energy of ATP hydrolysis.
26
 Import of proteins into mitochondria.
Proteins are targeted for mitochondria by
sequence containing positively charged
amino acids. Proteins are maintained in a
partially unfolded state by a cytosolic
Hsp70 and are recognized by a receptor on
the surface of mitochondria. The unfolded
polypeptide chains are then translocated
through the Tom complex in the outer
membrane and transferred to the Tim
complex in the inner membrane. The
voltage component of the electrochemical
gradient is required for translocation across
the inner membrane. The presequence is
The protein translocators in the mitochondrial membranes. The TOM, TIM, SAM, and OXA
complexes are multimeric membrane protein assemblies that catalyze protein translocation across cleaved by a matrix protease, and a
mitochondrial membranes. The protein components of the TIM22 and TIM23 complexes that line the mitochondrial Hsp70 binds the polypeptide
import channel are structurally related, suggesting a common evolutionary origin of both TIM chain as it crosses the inner membrane,
complexes. On the matrix side, the TIM23 complex is bound to a multimeric protein complex driving further protein translocation. A
containing mitochondrial hsp70, which acts as an import ATPase, using ATP hydrolysis to pull proteins mitochondrial Hsp60 then facilitates
through the pore In animal cells, subtle variations exist in the subunit composition of the translocator folding of the imported polypeptide within
complexes to adapt the mitochondrial import machinery to the particular needs of specialized cell types. the matrix.
SAM = Sorting and Assembly Machinery; OXA = cytochrome OXidase Activity; TIM = Translocator
of the Inner Mitochondrial membrane; TOM = Translocator of the Outer Membrane.

Sorting proteins to the intermembrane space. Proteins can be targeted to the

Insertion of mitochondrial membrane proteins. Proteins targeted for the
mitochondrial membranes contain hydrophobic stop-transfer sequences that halt
their translocation through the Tom or Tim complexes and lead to their
incorporation into the outer or inner membranes, respectively.
intermembrane space by several mechanisms. Some proteins (I) are translocated
through the Tom complex and released into the intermembrane space. Other proteins
(II) are transferred from the Tom complex to the Tim complex, but they contain
hydrophobic stop-transfer sequences that halt translocation through the Tim complex.
These stop-transfer sequences are then cleaved to release the proteins into the
intermembrane space. Still other proteins (III) are imported to the matrix. Removal of
the presequence within the matrix then exposes a hydrophobic signal sequence, which
targets the protein back across the inner membrane to the intermembrane space.

EKC 2017 27
 Protein import pathways into mitochondria. Most mitochondrial proteins are synthesized in the
cytosol. With the help of cytosolic chaperones, mitochondrial precursor proteins are transferred to the
general entry gate of mitochondria, the TOM complex, from where they are subsequently sorted into one
of the mitochondrial sub-compartments. The precursors of  -barrel outer membrane proteins require the
SAM complex. Preproteins destined for the matrix depend on the presequence translocase (TIM23
complex) and its associated import motor (PAM complex) for their transport across the inner
mitochondrial membrane. Carrier proteins are inserted into the inner membrane with the help of the
carrier translocase (TIM22 complex). OM, outer membrane; IMS, intermembrane space; IM, inner
membrane. (JBC 279:14473, 2004)

EKC 2017 28
 Schmidt et al. 2010 Nature Rev Mol Cell Biol. 11:655-667

Figure 1. Biogenesis pathways of mitochondrial proteins. Most mitochondrial proteins are synthesized on cytosolic
ribosomes and imported through the translocase of the outer mitochondrial membrane (TOM) complex (1). After
passage through the TOM channel, the precursor proteins can use different sorting machineries (2). Presequence-
carrying proteins destined for the matrix are imported by the presequence translocase of the inner membrane (TIM23) Phospholipid profile of ER and mitochondrial membranes in yeast S. cerevisiae. CL,
complex and presequence translocase-associated motor (PAM). Mitochondrial processing peptidase (MPP) removes cardiolipin; PA, phosphatidic acid; PC, phosphatidylcholine; PE,
the presequences (3). Some proteins are laterally released from the TIM23 complex into the lipid phase of the inner
phosphatidylethanolamine; PI, phosphatidylinositol; PS, phosphatidylserine; PG,
membrane (4). The mitochondrial intermembrane space assembly (MIA) machinery drives the import and oxidative
folding of many intermembrane space proteins (5). The Tim9–Tim10 chaperone complex transfers hydrophobic phosphatidylglycerol; IM, inner membrane; IMS, intermembrane space; OM, outer
precursor proteins through the intermembrane space to either the sorting and assembly machinery (SAM) complex, in membrane; ER, endoplasmic reticulum; CS, contact site.
the case of β-barrel proteins of the outer membrane (6), or through the carrier pathway to the TIM22 complex (7). The
precursors of α-helical outer membrane proteins do not use the TOM channel but are inserted into the membrane by
different pathways, some involving mitochondrial import 1 (Mim1; 8). A few proteins are synthesized on matrix
Tatsuta, T.& T. Langer, T. 2017 Biochimica et Biophysica Acta 1862: 81–89
ribosomes and are exported into the inner membrane by the oxidase assembly (OXA) machinery (9).

EKC 2017 29
 Asymmetric distribution of phospholipids in the outer
and inner mitocondrial membrane. Transbilayer
orientation of phospholipids in the outer mitocondrial
membrane (OMM) of the yeast Saccharomyces cerevisiae
(A) and rat liver (B) is indicated as % of individual
phospholipid facing the cytosolic side or the intermembrane
space (IMS), respectively. (C) Asymmetric distribution of
phospholipids in the inner mitochondrial membrane (IMM)
from mammalian cells is expressed as % of individual
phospholipids distributed between intermembrane space
(IMS) and the matrix side. PC, phosphatidylcholine; PE,
phosphatidylethanolamine; PS, phosphatidylserine; PI,
phosphatidylinositol; CL, cardiolipin. Data from Sperka-
Gottlieb et al. [36]; Hovius et al. [37]; Daum and Vance [5].

Horvath,S.E. & Daum G. 2013 Progress in Lipid Research 52: 590–614 Horvath,S.E. & Daum G. 2013 Progress in Lipid Research 52: 590–614

Phospholipid exchange proteins.

Because phospholipids are insoluble in
water, their passage between
membranes requires carrier proteins.
Phospholipid exchange proteins are
water-soluble proteins that carry a
single molecule of phospholipid at a
time; they can pick up a lipid molecule
from one membrane and release it at
another, thereby redistributing
phospholipids between membrane-
enclosed compartments. The net
transfer of phosphatidylcholine (PC)
from the ER to mitochondria can occur
without the input of additional energy,
because the concentration of PC is high
in the ER membrane (where it is made)
and low in the outer mitochondrial
membrane..
The synthesis of phosphatidylcholine. This phospholipid is synthesized from
glycerol 3-phosphate, cytidine-bisphosphocholine (CDP-choline), and factty
acids delivered to the ER by fatty acid binding protein.

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 Horvath,S.E. & Daum G. 2013
Progress in Lipid Research
52: 590–614

Phosphatidylethanolamine (PE) and cardiolipin (CL) biosynthesis in yeast, mammalian cells and plants.
Biosynthetic pathways in yeast (1), plants (2) and mammalian cells (3) are shown. Steps without numbering are found
in all types of cells. Ale1, acyltransferase for lyso-PE; CDP-DAG, CDP-diacylglycerol; Cds1, CDP-diacylglycerol
synthase; Cld1, cardiolipin-specific deacylase; Crd1, cardiolipin synthase; Dpl1, dihydrosphingosine phosphate lyase;
Ect1, ethanolaminephosphate cytidylyltransferase; Eki1, ethanolamine kinase; Ept1, sn-1,2-diacylglycerol
ethanolaminephosphotransferase; Etn, ethanolamine; EtnP, ethanolaminephosphate; Gep4, genetic interactors of
prohibitins; IMM, inner mitochondrial membrane; MLCL, monolysocardiolipin; OMM, outer mitochondrial membrane;
PA, phosphatidic acid; PG, phosphatidylglycerol; PGP, phosphatidylglycerolphosphate; Pgs1,
phosphatidylglycerolphosphate synthase; PLD, phospholipase D; PS, phosphatidylserine; Psd, phosphatidylserine
decarboxylase; Pss2, phosphatidylserine synthase-2; Sdc, serine decarboxylase; Ser, serine; Tam41, translocator
assembly and maintenance protein 41; Taz1, taffazin; Tgl3, triacylglycerol lipase.
Lipid trafficking at mitochondria. The synthesis of cardiolipin (CL), phosphatidylethanolamine (PE), and steroid
hormones occurs at the inner membrane (IM) and requires the import of precursor lipids from the endoplasmic
reticulum (ER) at mitochondria-associated membranes (MAMs). Newly synthesised lipids are redistributed between
mitochondrial membranes or exported from the organelle. Blue arrows represent lipid efflux; black thick arrows
represent conversion of lipids. Phospholipid synthesising enzymes from the IM of yeast mitochondria are shown.
CDP-DAG, cytidine diphosphate-diacylglycerol; Crd1, cardiolipin synthase; Gep4, phosphatidylglycerolphosphate
phosphatase; OM, outer membrane; PA, phosphatidic acid; Pgs1, phosphatidylglycerolphosphate synthase; P450scc,
cytochrome P450 side chain cleavage enzyme, which converts cholesterol to pregnenolone in steroidogenic
mitochondria; PC, phosphatidylcholine; PGP, phosphatidylglycerolphosphate; PI, phosphatidylinositol; PS,
phosphatidylserine; Psd1, phosphatidylserine decarboxylase; Tam41, CDP-DAG synthase.
Tatsuta T. et al. 2014 Trends in Cell Biology 21(1): 44-52

Phospholipid transport processes associated with mitochondrial membranes. (A) CL biogenesis and
remodeling. CL biogenesis depends on the supply of precursor lipids from the ER. Ups1-Mdm35 (PRELID1-
TRIAP1 in humans) transfers PA across the IMS. The transferred PA is converted to CL by the enzymatic
cascades in the IM. Other plausible transport processes in these cascades remain largely uncharacterized
(depicted by question marks). (B) Induced CL externalization signals cellular events. When mitochondria
encounter stress insults, CL in the IM is mobilized to the OMand is exposed to the outer surface of mitochondria.
The process depends on the activities of NDPK-D,MtCK and PLS3. Externalized CL induces cellular events to
cope with stresses.
Tatsuta, T.& T. Langer, T. 2017 Biochimica et Biophysica Acta 1862: 81–89

EKC 2017 31
 Mitochondrial and nuclear DNA stained with a fluorescent dye.
The micrograph shows the distribution of the nuclear genome (red)
and the multiple small mitochondrial genomes (bright yellow spots) 1 m
in a Euglena gracillis cell

Tamaño del genoma de los organelos

Tipo de DNA Tamaño (kbp)
DNA de cloroplastos
Plantas superiores 120-200 Cantidades relativas de DNA de organelos en algunos tejidos y tipos celulares
Chlamydomonas (alga verde) 180 Moléculas de Número de DNA del organelo
Organismo Tejido o DNA por organelos por como % del DNA
DNA de mitocondrias tipo celular organelo célula total
Animales (gusanos planos,insectos, mamíferos) 16-19
DNA de mitocondrias
Plantas superiores 150-2500
Rata hígado 5-10 1000 1
Hongos
Schizosaccharomyces pombe 17 Levadura* vegetativa 2-50 1-50 15
Aspergillus nidulans 32 Xenopus laevis oocito 5-10 107 99
Neurospora crassa 60 DNA de cloroplastos
Saccharomyces cerevisiae 78
Chlamydomonas vegetativa 80 1 7
Chlamydomonas (alga verde)* 16
Protozoos
Maíz hojas 20-40 20-40 15
Trypanosoma brucei 22 * la gran variación en el número y tamaño se debe a fragmentación y fusión mitocondrial
Paramecium* 40
* moléculas lineales

EKC 2017 32

Comparison of mitochondrial genomes. Less complex mitochondrial
genomes encode subsets of the proteins and ribosomal RNAs that are encoded
by larger mitochondrial genomes. The five genes present in all known
mitochondrial genomes encode ribosomal RNAs (rns and rnl), cytochrome b
(cob), and two cytochrome oxidase subunits (cox1 and cox3). (Adapted from
M.W. Gray et al., Science 283:1476–1481, 1999.)
PEROXISOMAS
EKC 2017
The organization of the human mitochondrial genome. The genome contains 2
rRNA genes, 22 tRNA genes, and 13 protein-coding sequences. The DNAs of
many other animal mitochondrial genomes have also been completely sequenced.
Most of these animal mitochondrial DNAs encode precisely the same genes as
humans, with the gene order being identical for animals that range from mammals
to fish
An electron micrograph of three peroxisomes in a rat liver cell. The paracrystalline
electron-dense inclusions are composed of the enzyme urate oxidase. (Courtesy of Daniel S.
Friend.) Peroxisomes are unusually diverse organelles containing different set of enzymes
33
 Los peroxisomas son organelos
pequeños delimitados por una
membrana

Tienen morfología similar a la de los

lisosomas
Las proteínas del lumen de los
peroxisomas se fabrican en ribosomas
“libres” y se importan al organelo de
manera post-traduccional
No poseen DNA ni ribosomas pero
experimentan fisión
El contenido de las enzimas presentes en su
interior puede variar enormemente
dependiendo del organismo en que se
estudian

Funciones de los peroxisomas Funciones de los peroxisomas

Originalmente se los describió como organelos que efectúan

reacciones que producen H2O2 Colesterol y dolicol se sintetizan en peroxisomas de células
animales (también en el retículo)
Poseen unas 50 enzimas diferentes
Oxidan ácido úrico (urato oxidasa), aminoácidos (mono Síntesis de ácidos biliares en el hígado
amino oxidasa) y ácidos grasos de cadena larga (más de 20
átomos de carbono) (producción de calor) Síntesis de plasmalógenos (importantes en el tejido cardíaco
y en el cerebro)
Destoxificación de moléculas tóxicas en el hígado
En vegetales y levaduras la oxidación de ácidos grasos ocurre Glicosomas en Trypanosoma cruzi y Tripanosoma brucei
sólo en los peroxisomas
Etapas finales de la síntesis de penicilinas (hongos)

EKC 2017 34
 P

Structure of a plasmalogen. The plasmalogen shown is analogous to phosphatidylcholine.

Fatty acid oxidation in peroxisomes. The oxidation of a fatty acid is accompanied by the production
of hydrogen peroxide (H2O2) from oxygen. The hydrogen peroxide is decomposed by catalase, either
by conversion to water or by oxidation of another organic compound (designated AH2).
However, one of the fatty acid chains is joined to glycerol by an ether, rather than an ester, bond.
Plasmalogens are important membrane components in some tissues, particularly heart and brain,
although they are absent in others. Plasmalogens are synthesized in peroxisomes and are the
most abundant phospholipid in the myelin sheaths that insulate the axons of nerve cells. They
make up some 80-90% of the myelin membrane phospholipids.

Enzimas y vías metabólicas en diferentes tipos de peroxisomas

Mamíferos Levaduras Semillas Trypanosoma

-oxidación ácidos grasos + + + +

Catalasa + + + +

Síntesis de éter-fosfolípidos + - - +

Glicolisis - - - +

Ciclo del glioxilato - + + -

Síntesis de isoprenoides + - ? ?

Reutilización de purinas - - - +

(+) Presencia; (-) Ausencia; (?) Se desconoce

Smith JJ & Aitchison JD 2013

Adaptado de Salceda R. 2008, REB 27(3):85-92
Nature Rev. Mol Cell Biol 14:803 - 817

EKC 2017 35

The interdependence of peroxisomes, ER, and mitochondria in
lipid metabolism
Mast, FD et al. Physiology 2010 25:347-356
Protein traffic to the peroxisome. Under the old model (Lazarow and Fujiki 1985), peroxisomal
membrane proteins (PMPs) target to the organelle after translation on cytosolic ribosomes. Recent
evidence, however, argues that PMPs are first inserted into the endoplasmic reticulum (ER) via either
the Sec61 translocon or the GET (Get1p/Get2p/Get3p) complex. Subsequently, the PMPs exit the ER
to reach the peroxisome. There is consensus in the literature that peroxisomal matrix proteins target to
the organelle after translation on cytosolic ribosomes.
Dimitrov L et al. 2013 Cold Spring Harb Perspect Biol;5:a013243
EKC 2017
Gabaldón T 2010 Phil. Trans. R. Soc. B 365:365–773
A schematic view of the peroxisome. The biogenesis and maintenance processes (full-line boxes),
which comprise the proteins involved in protein import and organelle division, are present in all types
of peroxisomes. The enzymatic content of the peroxisome (dashed-line boxes) is highly variable, with
different enzymatic sets being present in different species. Enzymes involved in fatty acid metabolism
and reactive oxygen species detoxification are widespread. Other additional pathways (in blue) might
be restricted to certain groups of eukaryotes. The text at the right-hand side of the figure provides some
important remarks about the diversity and evolution of each depicted process.
A model that explains how peroxisomes proliferate and how new peroxisomes may arise.
Peroxisome precursor vesicles are thought to bud from ER. The machinery that drives the budding
reaction and selects only peroxisomal proteins fotr packaging into these vesicles – and not, for
example, ER proteins- is not known. Peroxisome precursor vesicles may then fuse with one another
or with preexisting peroxisomes. The persoxisome membrane contains import receptor proteins which
are maded by cytosolic ribosomes. Presumably, the lipids required for growth are also imported,
although some may derive directly from ER in the membrane of peroxisome precursor vesicles.
36
 Generalized models for the flow of membrane-enclosed carriers
through the peroxisomal endomembrane system in yeast,
mammals, and plants. PPT, preperoxisomal template; PPV,
preperoxisomal vesicle; SV, secretory vesicle; TBSV p33, TSBV 33-
kD replicase protein. (Titorenko & Mullen 2006, JCB 174(1):11-17)

External (Enviromental stimuli i.e. diet rich in substances

requiring metabolism by peroxisomes)
Peroxisomal proliferation

Internal (Cell need’s to increase its organelle population in

response to cell division)

Peroxisome division. Peroxisome

division can be symmetrical or
Assembly of peroxisomes. Proteins destined for peroxisomes are
asymmetrical. After receiving a
synthesized on free ribosomes and imported into preexisting
peroxisomes as completed polypeptide chains. Protein import signal to divide, peroxisomes
results in peroxisome growth and the formation of new elongate and are constricted into
peroxisomes by division of old ones. divisible units, making them
competent for the final scission
event. Whether symmetric or
asymmetric division represents the
primary mode of peroxisome
division and whether peroxisome
division, irrespective of the mode of
cleavage, leads to matrix protein
asymmetry remain unresolved.

Mast, FD et al. Physiology 2010 25:347-356

EKC 2017 37

Smith JJ & Aitchison JD 2013 Nature Rev. Mol Cell Biol 14:803 - 817
Peroxisomes can form through two pathways. Details
of peroxisome formation by de novo generation, and by
growth and division are shown for yeast. Peroxisomes Synthesis of catalase and its incorporation
are formed de novo from the endoplasmic reticulum into peroxisomes. Newly made catalase
(ER) through budding and pair-wise heterotypic fusion
of two vesicle types, V1 and V2 (left). This mechanism
subunits are released from polyribosomes into
separates RING finger and docking components of the the cytosol as apocatalase, a monomer that
import complex into different vesicles, which are not contains a C-terminal SKL uptake-targeting
import competent until after fusion and assembly of a sequence (red) but lacks an iron-containing
complete and functional import complex. Peroxin 1
(Pex1) and Pex6 are found in separate preperoxisomal heme group. Step 1: Four monomers are
vesicles and are necessary for the heterotypic fusion of assembled and heme is added, forming the
V1 and V2 vesicles and the formation of mature, import- mature tetrameric catalase molecule. Steps 2
competent peroxisomes. Mature peroxisomes can
multiply by growth, with proteins and membranes from
and 3: The cytosolic receptor protein PTS1R
the ER (via V3 vesicles; right), and fission, mediated by binds an SKL signal and escorts the catalase
Pex11. Although all preperoxisomal vesicles tetramer to the Pex14p receptor on the
characterized contain Pex3 (which is required for peroxisome membrane. In the model depicted
egression from the ER), V3 vesicles are distinct from V1
and V2 vesicles because they can fuse with mature here, the catalase-PTS1R complex is
peroxisomes. A fission cycle begins with membrane transported across the membrane and then
remodelling and elongation mediated by Pex11. dissociates in the lumen. As-yet
The elongated extension grows and acquires DRP
(dynamin-related protein)-interacting proteins (including
uncharacterized proteins on the peroxisomal
the fission protein Fis1. The membrane becomes membrane probably form part of the receptor-
constricted by an unknown mechanism, and DRPs transport channel. Step 4: PTS1R returns to
(Dnm1 and vacuolar sorting protein 1 (Vsp1) in yeast or the cytosol to pick up another peroxisome-
dynamin-like protein DLP1 in mammalian cells), which
are recruited from the cytosol by DRP-interacting destined protein. In an alternative model,
proteins, facilitate membrane fission to generate new PTS1R delivers catalase to the Pex14p
peroxisomes. Note that for simplicity, not all peroxins receptor but does not enter the lumen itself.
are shown.

Electron micrographs of two types of peroxisomes found in plant cells. (A) A peroxisome with
a paracrystalline core in a tobacco leaf mesophyll cell. Its close association with chloroplasts is
thought to facilitate the exchange of materials between these organelles during photorespiration.
(B) Peroxisomes in a fat-storing cotyledon cell of a tomato seed 4 days after germination. Here,
the peroxisomes (glyoxysomes) are associated with the lipid bodies where fat is stored, reflecting
their central role in fat mobilization and gluconeogenesis during seed germination.

Smith JJ & Aitchison JD 2013 Nature Rev. Mol Cell Biol 14:803 - 817

EKC 2017 38
 Enfermedades asociadas con los peroxisomas
Síndrome de Zellweger: defecto en transporte de
proteínas de la matriz peroxisomal pero no de la
proteínas de la membrana del organelo
Adrenoleucodistrofia (ligada a X): ácidos grasos
de cadena larga son esterificados a la CoA en la
matriz del peroxisoma. Falla el transporte de la
enzima que cataliza esa reacción
Smith JJ & Aitchison JD 2013 Nature Rev. Mol Cell Biol 14:803 - 817
EKC 2017
Dm, Drosophila melanogaster; Hp, Hansenula
polymorpha, Hs, Homo sapiens; Mm, Mus
musculus; Saccharomyces cerevisiae; Yl,
Yarrowia lipolytica Nc, Neurospora crassa;
IRD, infantile refsum disease; NALD, neonatal
adrenoleukodystrophy; PEX, peroxin;
PBD, peroxisome biogenesis disorder; RCDP,
rhizomelic chondrodysplasia punctata; Sc,; ZS,
Zellweger syndrome; ZSS, ZS spectrum.
*Slow progression (diagnosed at 51 years)21.
‡Slow progression (diagnosed >30 years) with
late-onset leukodystrophy22. §This open reading
frame, YMR018W28, has a predicted role in
peroxisome biogenesis or function as indicated by
transcriptome profiling64. ||Slow progression
(diagnosed at 26 years) with ZSS-atypical
symptoms, including mild intellectual disability.
39