Hindawi Publishing Corporation

International Journal of Cell Biology

Volume 2012, Article ID 821676, 10 pages
doi:10.1155/2012/821676

Review Article
Mitochondrial Dynamics: Functional Link with Apoptosis

Hidenori Otera and Katsuyoshi Mihara

Department of Molecular Biology, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan

Correspondence should be addressed to Katsuyoshi Mihara, mihara@cell.med.kyushu-u.ac.jp

Received 30 November 2011; Accepted 17 January 2012

Academic Editor: Lina Ghibelli

Copyright © 2012 H. Otera and K. Mihara. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

Mitochondria participate in a variety of physiologic processes, such as ATP production, lipid metabolism, iron-sulfur cluster
biogenesis, and calcium buffering. The morphology of mitochondria changes dynamically due to their frequent fusion and division
in response to cellular conditions, and these dynamics are an important constituent of apoptosis. The discovery of large GTPase
family proteins that regulate mitochondrial dynamics, together with novel insights into the role of mitochondrial fusion and fission
in apoptosis, has provided important clues to understanding the molecular mechanisms of cellular apoptosis. In this paper, we
briefly summarize current knowledge of the role of mitochondrial dynamics in apoptosis and cell pathophysiology in mammalian
cells.

1. Introduction mitochondrial activity. Mitochondrial fission, on the other

hand, plays an important role in the quality control of mito-
Apoptosis, also called programmed cell death, is a crucial chondria, facilitating the removal of damaged mitochondria
physiologic process in the development and homeostasis of to maintain cellular homeostasis [6–10]. Compromise of this
multicellular organisms [1]. Perturbation of this vital process quality control system induces cell death, which results in
leads to a range of diseases, such as ischemia, cancer, neuro- various degenerative disorders [9]. Mitochondrial fission is
degeneration, and autoimmunity [2]. The mitochondrial also essential for the distribution of mitochondria in res-
outer membrane (MOM) serves to coordinate mitochondrial ponse to the local demand for ATP or calcium buffering [10].
function with extra mitochondrial signaling and participates In addition to these fundamental roles, the dynamic mor-
in the regulation of mitochondrial homeostasis. Mitochon- phologic changes of mitochondria are closely associated with
dria have a central role in the initiation of apoptosis trig- the initial process of apoptosis. The rate of fission increases
gered by intrinsic death signals such as DNA damage (the markedly when cells become committed to apoptosis; apop-
mitochondrial pathway) by releasing cytochrome c and other totic stimuli such as DNA injury, UV radiation, endoplasmic
apoptogenic factors stored in the intermembrane space reticulum (ER) stress, oxygen radicals, or cytokine with-
(IMS) into the cytoplasm [3, 4]. Cytochrome c complexed drawal trigger extensive mitochondrial fission accompanied
with Apaf-1 activates caspase 9, which leads to the activation by cristae disorganization and permeabilization of the mito-
of downstream caspases [5]. chondrial outer membrane (MOMP), which in turn induces
Mitochondrial morphology changes dynamically by con- the release of IMS-stored proapoptotic factors, such as cyto-
tinuous fission and fusion to form small units or intercon- chrome c, to trigger the apoptosis program [11–15]. Al-
nected mitochondrial networks, and the balance of these though modulation of mitochondrial fusion and fission
dynamic changes is essential for counteracting deleterious machineries is considered to influence the apoptotic response
mitochondrial processes. Mitochondrial fusion allows for of the cells, it remains controversial whether fission is abso-
complementation of damaged mitochondrial DNA and other lutely required for the progression of apoptosis. Nonetheless,
contents (e.g., lipids, proteins, or metabolites) with the com- perturbations of the mitochondrial dynamics cause cellular
ponents of healthy mitochondria, thus maintaining normal dysfunction, particularly of highly polarized cells such as
2 International Journal of Cell Biology

neurons, and neuronal synaptic loss and cell death in neu- fission in mammals. It is composed of an N-terminal GTPase
rodegenerative disorders (e.g., Alzheimer’s disease, Parkin- domain thought to provide mechanical force, a dynamin-
son’s disease, and Huntington’s disease), although the func- like middle domain, a connecting domain (“B” in Figure 1),
tional relation between the morphologic alterations and and a C-terminal GTPase effector domain (GED) (Figure 1).
apoptosis is still insufficiently understood [16]. Compared with mitochondrial fusion, however, the in vivo
function of Drp1-dependent mitochondrial fission is poorly
2. Regulation and Physiologic Significance of understood. During mitochondrial fission, Drp1 existing as
small oligomers in the cytoplasm assembles into larger oligo-
Mitochondrial Fusion and Fission
meric structures at the mitochondrial fission sites depending
Three types of high-molecular-weight GTPase proteins reg- on GTP binding and then severs the mitochondrial mem-
ulate mitochondrial fusion and fission in mammals [10]. brane by GTP hydrolysis. A heterozygous, dominant-nega-
Outer membrane fusion involves two mitofusin proteins tive mutation of the Drp1 gene (A395D in the middle
(Mfn1 and Mfn2; Fzo1 in yeast) located on the mitochon- domain) was identified in a newborn girl with severe pleio-
drial outer membrane (MOM) [17, 18]. An IMS-localized trophic defects, including abnormal brain development and
GTPase, OPA1 (Mgm1 in yeast), functions as a hetero-oligo- optic atrophy, who died at 37 days of age (Figure 1) [31].
meric complex of the larger size Opa1 (L-Opa1) and the To elucidate the detailed physiologic roles of mitochondrial
smaller size Opa1 (S-Opa1) in fusion and cristae organiza- fission in vivo, we and another group generated tissue-
tion of the inner membrane (MIM) [19, 20]. The cytoplas- specific Drp1 KO mice [32, 33]. Drp1 KO mice die at around
mic dynamin-related GTPase protein Drp1 (Dnm1 in yeast) E12.5 with developmental abnormalities, particularly in the
translocates to the foci of future mitochondrial fission sites forebrain. Neuron-specific Drp1 KO mice are born, but die
and mediates mitochondrial fission [21–23]. Mitochondrial within a day of birth due to neurodegeneration, although
fission factor (Mff), and mitochondrial dynamics (Mid) 51/ Drp1 is dispensable for the viability of mouse embryonic
mitochondrial elongation factor 1 (MIEF1), and the variant fibroblast (MEF) cells. In primary cultured neural Drp1 KO
Mid49 were recently reported to function as Drp1 receptors cells, enlarged mitochondrial clumps are sparsely distributed
on the MOM [10, 24–27], although detailed mechanisms of in the neurites and the synaptic structures are lost. These
Mff and MiD/MIEF1 proteins and their relation in Drp1- findings suggest that the Drp1-deficiency causes the abnor-
dependent mitochondrial fission remain to be clarified. The mal distribution of fused and aggregated mitochondria in
function of the mammalian homolog of yeast Fis1, which is polarized cells and these spatiotemporal defects might inhibit
thought to regulate mitochondrial fission as in yeast remains the ATP supply and Ca2+ signaling, eventually preventing
controversial [10, 24, 25]. synapse formation. Similarly, Drp1-dependent mitochon-
Mutations in the mitochondrial fusion factors Mfn2 and drial fission is essential for immune synapse formation in T-
OPA1 result in neurodegenerative disorders, such as Char- cell receptor signaling [34]. A missense mutation in mouse
cot-Marie-Tooth Neuropathy 2a and Dominant Optic Atro- Drp1 in the middle domain, which is essential for oligomer-
phy I, respectively [16, 19, 20]. Mitochondrial fusion factor ization (Python mice; C452F mutation), leads to cardiomy-
knockout (KO) mice are lethal before embryonic day 12.5 opathy [35]. The physiologic relevance of Drp1 in other
(E12.5 for Mfn1 KO) or embryonic day 11.5 (E11.5 for Mfn2 tissues that might underlie various human diseases remains
KO), suggesting that both Mfn isoforms are essential for to be elucidated.
embryonic development in mammals [17]. Cells lacking Drp1 activity is regulated by various posttranslational
both Mfn1 and Mfn2 exhibit severe cellular defects, includ- modifications and changes in these modifications are related
ing poor cell growth, heterogeneity of inner membrane po- to several disorders (Figure 1). In the early mitotic phase,
tential, and decreased respiration, indicating that mitochon- Ser616 in human Drp1 is specifically phosphorylated by the
drial fusion has an essential role in maintaining functional Cdk1/cyclinB complex, which promotes mitochondrial fis-
mitochondria. Depletion of Mfn2 in neurons in mice leads sion to facilitate stochastic distribution of the mitochondria
to highly specific degeneration of Purkinje neurons [17]. to daughter cells [36]. Under oxidative stress conditions, pro-
The mitochondria in these mutant cells are fragmented and tein kinase Cδ mediates phosphorylation of Ser579 in human
fail to distribute to the long and branched neurites, indi- Drp1 isoform 3 (Ser616 in the human Drp1 isoform 1),
cating that fusion also plays an important role in mito- leading to mitochondrial fission and impaired mitochondrial
chondrial distribution in polarized cells. Depletion of both function, which contributes to hypertension-induced brain
Mfn isoforms in skeletal muscle results in muscle atrophy injury [37]. Phosphorylation at Ser637 in the GED domain
[28]. Homozygous mutation of OPA1 in mice leads to of human Drp1 by cAMP-dependent protein kinase (PKA)
embryonic lethality by E13.5 in mice, while heterozygous stimulates Drp1 GTPase activity and releases Drp1 from
mutation causes a slow onset of degeneration in the optic the mitochondria by inhibiting oligomeric assembly on the
nerves [29]. Pancreatic beta-cell-specific OPA1 KO mice have membrane to promote mitochondrial network extension and
compromised glucose-stimulated insulin secretion and ATP cell viability [38]. This reaction is reversed by calcineurin-
production due to a defect in respiratory complex IV, sug- mediated dephosphorylation [39, 40]. Polyglutamine expan-
gesting that the function of OPA1 in the maintenance of the sions in huntingtin protein, the cause of Huntington’s dis-
respiratory chain is physiologically relevant to beta cells [30]. ease, superactivate calcineurin through enhanced calcium
The dynamin-related GTPase Drp1 localizes mainly in levels, and increase mitochondrial recruitment of Drp1,
the cytoplasm and plays a central role in mitochondrial leading to apoptosis due to mitochondrial fission, cristae
International Journal of Cell Biology 3

Apoptosis
(hypertension-induced brain injury)

Oxidative stress
Fission
PKCδ β-amyloid protein

P NO
(Lethal disease) Synaptic loss
A395D S616 C644 Fission apoptosis
N GTPase Middle B GED C
S637
P Fission Cell survive

PKA Fission Apoptosis

Calcineurin

Q Q Q -huntingtin
Q
Q
QQ

Figure 1: Domain structure of Drp1 and schematic view of the regulation of Drp1 by posttranslational modifications. Drp1 activity is
regulated by various posttranslational modifications and changes in these modifications are related to several disorders. Under oxidative
stress, protein kinase Cδ (PKCδ) phosphorylates Drp1 at Ser616 in the GED domain. Drp1 is recruited to mitochondria and stimulates
mitochondrial fission, leading to apoptosis in hypertension-induced brain. Cyclic-AMP-dependent protein kinase (PKA) phosphorylates
Drp1 at Ser637 in the GED domain. This reaction releases Drp1 from mitochondria to the cytosol, leading to mitochondrial elongation and
suppression of apoptosis vulnerability of the cells. Calcineurin dephosphorylates Drp1 at Ser637 and promotes mitochondrial fragmentation
and cell vulnerability to apoptosis. Polyglutamine expansion in huntingtin protein activates calcineurin and increases mitochondrial frag-
mentation and cell vulnerability to apoptosis. β-Amyloid protein increases S-nitrosylation of Drp1 at Cys644 in the GED domain to trigger
mitochondrial fission by activating GTPase, thereby causing synaptic loss. All amino acid numbering is based on the human Drp1 splice
variant 1 sequence.

disintegration, and cytochrome c release (Figures 1 and 3) an intrinsic (mitochondrial) pathway where mitochondria
[41]. Further, mutant huntingtin protein directly binds Drp1 play a central role governed by pro- and antiapoptotic Bcl-2
and increases its GTPase activity, leading to mitochondrial family proteins. The extrinsic pathway does not directly
fragmentation and defects in anterograde and retrograde involve the mitochondria, and activation of the initiator
mitochondrial transport and neuronal cell death [42, 43]. β- caspase (caspase-8) is mediated by the death-inducing sig-
Amyloid protein, a key mediator of Alzheimer’s disease, is naling complex [47]. Conversely, the intrinsic pathway is
reported to induce S-nitrosylation of Drp1 at Cys644 in the initiated by the release of cytochrome c from the IMS accom-
GED domain to trigger mitochondrial fission by activating panied by MOMP and cristae disorganization, which acti-
GTPase and thereby causing synaptic loss (Figure 1) [44], vates procaspase-9 through Apaf-1 [3, 4, 15]. Although the
although this model has been challenged [45]. Thus, mito- extrinsic and intrinsic pathways have long been considered
chondrial morphologic balance shift toward fission makes independent from each other, evidence that caspase-8 also
cells susceptible to apoptosis and vice versa (Figure 1). activates the intrinsic pathway has led to a more complex
view of apoptosis in which crosstalk exists between the two
pathways [48, 49].
3. Regulation of Mitochondrial Apoptosis by The Bcl-2 family proteins regulate the MOM integrity
Bcl-2 Family Proteins and contribute to the release of proapoptotic factors from the
IMS to the cytoplasm by MOMP [50, 51]. Irrespective of the
Mitochondria play a central role in apoptotic initiation by precise mechanism, the antiapoptotic members of the Bcl-2
providing proapoptotic factors that are involved in caspase family tend to stabilize the barrier function of the MOM,
activation, and chromosome condensation and fragmenta- whereas proapoptotic Bcl-2 family proteins such as Bax or
tion [15]. Multiple cellular pathways trigger apoptosis [46]: Bak tend to antagonize such function and permeabilize the
an extrinsic pathway that is initiated by the binding of a death MOM. Upon apoptotic stimuli, caspase-8 activated by the
ligands to the plasma-membrane-localized receptor, result- death-inducing signaling complex cleaves the proapoptotic
ing in the rapid activation of caspases in the cytoplasm and BH3-only protein Bid to the active truncated form (tBid).
4 International Journal of Cell Biology

The activated tBid is then recruited to the cardiolipin-rich

III: smac/DIABLO, HtrA2 release
region on the MOM by MTCH2, a half-type carrier super-
No cytochrome c release
family protein [52]. tBid either interacts with antiapoptotic
Bcl-2 family proteins such as Bcl-2 or Bcl-XL to inhibit their II: delayed cytochrome c release
MOMP
antiapoptotic functions [48, 49, 53], or triggers targeting Smac/DIABLO release III
and oligomerization of cytoplasmic Bax into the MOM and HtrA2 release
Opa1-dependent cristae disorganization, leading to the re-
II
lease of IMS-stored proapoptotic factors such as cytochrome
c [54]. Bak, in contrast to Bax, is constitutively localized in I
the MOM associating with voltage-dependent anion channel Cristae Fragmentation
disorganization
2 (VDAC2) as an inactive form in the ∼400-kDa complex,
and tBid activates Bak by releasing it from the complex,
leading to MOMP [55–58]. Bcl-XL interacts with Bax on the
I: cytochrome c release
mitochondrial surface and retrotranslocates it to the cytosol, Smac/DIABLO release
thereby preventing Bax-induced MOMP in healthy cells HtrA2 release
[59]. As discussed below, mitochondrial membrane dynam-
ics have an important role in the regulation of MOMP and Figure 2: Relation between mitochondrial structural changes and
apoptosis. the release of IMS-stored apoptogenic factors. During apoptosis in
wild-type cells, mitochondrial fragmentation normally occurs con-
comitantly with MOMP, cristae disorganization, and subsequent
4. The Role of Mitochondrial release of the IMS-stored apoptogenic factors (e.g., cytochrome c,
smac/DIABLO, HtrA2/omi). Mitochondrial fission facilitates these
Fission in Apoptosis reactions (State I). In contrast, elongated but cristae-disrupted
mitochondria (i.e., Drp1- and OPA1-double RNAi cells; Drp1-
It is generally accepted that the mitochondrial network
KO and OPA1 RNAi cells) exhibit a significant delay only in the
collapses into small spherical structures in response to apop- cytochrome c release in response to apoptotic stimuli, because of
totic stimuli, and that proapoptotic and antiapoptotic Bcl-2 the absence of mitochondrial fragmentation. Of note, however,
family member proteins play important roles in regulating MOM targeting and oligomeric assembly of Bax and the release of
mitochondrial morphology [15]. During apoptosis, cytosolic the IMS-soluble Smac/DIABLO normally proceed (State II). State
Bax is recruited to the MOM and colocalizes with Drp1 III: presumed MOM permeabilized state in the absence of both
and Mfn2 at mitochondrial sites where fission subsequently cristae disorganization and mitochondrial fragmentation. MOMP:
occurs [60]. Bak, which initially localizes uniformly on the mitochondrial outer membrane permeabilization.
MOM, also coalesces into discrete foci at mitochondrial fis-
sion sites during apoptosis. tBid-triggered Bax/Bak activation
correlates with a reduction in mitochondrial fusion, possibly
through the inhibition of Mfn2 and eventually leads to mito- mitochondrial fission during apoptosis; for example, Dro-
chondrial fragmentation [61, 62]. Upon Bax activation, Drp1 sophila PMI and its human homolog TMEM11 of MIM, both
stably associates with the MOM through Bax/Bak-dependent of which regulate mitochondrial morphology in a manner
SUMO modifications of Drp1 [63]. This mitochondrial independent of Drp1 and Mfn [67]. Taken together, these
fragmentation is caspase independent and occurs concomi- findings indicate that the delay in cytochrome c release in
tantly with MOMP, cristae disorganization, and subsequent these cells is relatively modest, suggesting that the Drp1-Mff
cytochrome c release (Figure 2) [64, 65]. Increased mito- system is dispensable, but facilitates the normal progression
chondrial fission in apoptotic cells apparently parallels the of apoptosis [32, 33]. Conversely, the inhibition of mito-
release of cytochrome c, and inhibition of fission by Drp1- chondrial fragmentation by the activation of fusion-related
RNA interference (RNAi) delays the release of cytochrome c, proteins, such as Mfn1, Mfn2, or Opa1 antagonizes apoptosis
suggesting that the release of cytochrome c from the IMS is progression.
intimately involved in mitochondrial fission [65]. Consistent A pharmacologic inhibitor of Drp1-GTPase, mdivi-1,
with these data, Mff depletion by RNAi results in extensive inhibits tBid-dependent cytochrome c release from isolated
mitochondrial elongation, delayed cytochrome c release, and mitochondria that are incapable of undergoing fission in
retardation of apoptosis [24, 66]. Similarly, MEFs from vitro. These findings suggest either that mdivi-1 inhibits
Drp1-KO mice exhibit a delay in cytochrome c release, cas- other Drp1 functions than mediating mitochondrial fission
pase activation and nuclear DNA fragmentation [32, 33]. or that it inhibits molecules other than Drp1 that regulate
Notably, mitochondria with network structures that are cytochrome c release [68]. Martinou and coworkers recently
subtly different from the structures observed prior to cyto- demonstrated that Drp1 promotes the formation of a non-
chrome c release are frequently detected in Drp1 KO cells bilayer hemifission intermediate in which the activated and
after the release of cytochrome c and seem to undergo frag- oligomerized Bax forms a hole, leading to MOMP [69].
mentation in the advanced stage of apoptosis, suggesting Therefore, although mitochondrial fragmentation is in-
that Drp1-independent mitochondrial fragmentation likely deed associated with apoptosis, excessive mitochondrial frag-
occurs late after the release of cytochrome c [32]. This sug- mentation can occur in a variety of conditions independently
gests that Drp1-independent fission might participate in of apoptosis processes, such as that occurring upon exposure
International Journal of Cell Biology 5

to carbonyl cyanide m-chlorophenyl hydrazone (CCCP), action of the cells that is necessary for survival by increased
uncoupling agents that disrupt the electrochemical potential mitochondrial ATP production. Under nutrient starvation,
of the MIM [70]. Thus, how Drp1 contributes to apoptosis is mitochondrial fission is repressed in response to PKA-
an important issue for future studies. dependent Drp1 phosphorylation of Drp1 Ser637 due to
increased cAMP levels (Figure 1), resulting in elongation of
the mitochondria with a higher density of cristae and a
5. Cristae Remodeling and Apoptosis capacity for efficient ATP production. This response protects
Opa1, localizing in the inner membrane as a hetero-oligo- mitochondria from autophagosomal degradation and sus-
meric complex of large and small size forms, regulates MIM tains cell viability [76, 77]. Taken together, enhanced fusion
fusion and is necessary for maintenance of the cristae junc- in the mitochondrial fusion/fission balance promotes cell
tions independently of mitochondrial fusion. The majority survival. Alternatively, dysfunctional or damaged mitochon-
of cytochrome c is confined within the cristae folds and the dria are selectively eliminated by autophagic degradation
complete release and mobilization of cytochrome c in the (termed mitophagy): the process essential for maintaining
IMS require cristae remodeling or cristae-junction opening mitochondrial quality and cell function. For example, accu-
[71]. Opa1 depletion by RNAi leads to fragmented mito- mulation of a causal gene product of Parkinson’s disease,
chondria with disrupted cristae structures and an increase PTEN-induced mitochondrial protein kinase 1 (PINK1) on
in the sensitivity to the apoptotic stimuli [65, 72, 73]. Fur- depolarized mitochondria facilitates recruitment of cyto-
ther, during early apoptosis, the Opa1 hetero-oligomer is dis- plasmic Parkin, an E3 ubiquitin ligase, to mitochondria to
rupted, the cristae widen, and cytochrome c is released into initiate mitophagy [78–80]. The Parkin-PINK1 system thus
the IMS. Of note, we demonstrated that Opa1 RNAi HeLa monitors damaged mitochondria, and dysfunction of this
cells have disrupted cristae and efficient sensitivity to apop- mechanism is a possible cause of inflammation or Parkin-
tosis, based on the cytochrome c release. In contrast, Opa1/ son’s disease [81–86]. As it is thought that mitochondrial
Drp1 or Opa1/Mff double-RNAi cells have elongated but fission is related to the progression of mitophagy, inhibition
cristae-disrupted mitochondria, and exhibit a significant of mitochondrial fission by the dominant negative mutant of
delay in the cytochrome c release in response to apoptotic Drp1 or specific inhibitor of Drp1-GTPase mdivi-1 compro-
stimuli (State II in Figure 2) [24]. Importantly, however, mises Parkin-PINK1-dependent mitophagy [83]. Together,
mitochondrial targeting of Bax and the release of the IMS- mitochondrial fusion and fission are more likely to be in-
soluble Smac/DIABLO proceeded with the same kinetics as volved in mitochondrial quality control in healthy cells. A
in the control cells. Similarly, in Drp1 KO MEFs or Drp1 recent report demonstrated that the A-kinase anchoring pro-
RNAi HeLa cells, Bax/Bak-mediated MOMP occurs inde- tein 1 (AKAP1) localized on the MOM is involved in this
pendently of Drp1 and is separable from cytochrome c re- reaction. Thus, the PKA/AKAP1 complex-calcineurin system
lease. These results suggest that cristae disorganization and regulates mitochondrial morphology and cell viability by
mitochondrial fission as well as MOMP (State I in Figure 2) controlling the translocation of Drp1 to the mitochondria
are essentially required for efficient cytochrome c release and (Figure 1) [87].
each can limit the initial apoptosis progression. In contrast to
these observations, detailed analysis with transmission elec- 7. Communication between the Mitochondria
tron microscopy and three-dimensional electron microscope and ER in Apoptosis
tomography revealed that neither cristae reorganization nor
cristae-junction opening is required for the complete release In yeast, the ER mitochondria encounter structure (ERMES
of cytochrome c [74]. Thus, the requirement of Opa1- comprising cytosolic Mdm12, mitochondrial Mdm10,
dependent cristae remodeling for cytochrome c release re- Mdm34, and Gem1, and ER membrane protein Mmm1),
mains to be reconciled. identified by synthetic biology and biochemical approaches
[88–90], are involved in phospholipid transport. A similar
structure is expected to exist in mammalian cells; a mam-
6. Mitochondrial Morphologic Responses in malian homolog of yeast Gem1, MIRO, is detected in the
Cell Survival proximity of the ER-mitochondria [90]. Ca2+ is a key regu-
lator of not only cell survival but also cell death in response
Many lines of evidence indicate that the efficiency of oxi- to various apoptotic stimuli (Figure 3). The mitochondria
dative phosphorylation by the mitochondrial electron trans- and ER have close contacts that are physiologically important
port chain is affected by the degree of mitochondrial connec- for the transfer of Ca2+ , lipids, and metabolites, and there-
tivity; a highly connected mitochondrial network correlates fore, for the regulation of mitochondrial metabolism and
with increased ATP production efficiency. Mitochondria other complex cellular processes including apoptosis. Mfn2
hyperfuse and form a highly interconnected network when and its regulator Trichoplein/mitostatin localizing on the
cells are exposed to modest levels of stress (e.g., UV irra- mitochondria-associated ER membranes (MAM) is in-
diation, actinomycin D treatment), named stress-induced volved in tethering mitochondria and ER through hetero-
mitochondrial hyperfusion (SIMH) [75]. SIMH depends on or homotypic interactions with mitochondrial Mfn1 and
Mfn1, Opa1, and the MIM protein SLP-2, and delays the Mfn2, thereby regulating Ca2+ transfer from the ER to the
activation of Bax and MOMP similar to the beneficial effect mitochondria [91, 92]. Interactions between the mitochon-
of mitofusin overexpression. This seems to be a counterstress dria and ER are also supported by the finding that the ER
6 International Journal of Cell Biology

Nucleus
Ca2+
from ER to mitochondria Cytochrome c

ER Virus infection
SERCA
Bap31 ROS
Stress signal, etc.
Ca2+ influx

Casp-8
IP3R hFis1 Mfn2
p20Bap31
BiK
Mfn2
MICU1 Mfn1
LETM1

MAM Mfn1
Drp1-S637
Cristae remodeling P
Cytochrome c release

Mitochondrial
fragmentation Calcineurin

Bax/Bak
Drp1
recruitment
Drp1/Mff
Mitochondrial fragmentation Drp1-S637

Apoptosis

Figure 3: Hypothetical models of the role of contacts between mitochondria and ER in apoptosis. The hFis1/Bap31 platform transmits the
mitochondrial stress signal to the ER via the activation of procaspase-8. The cytosolic region of the ER integral membrane protein Bap31
is cleaved by activated caspase-8 to generate proapoptotic p20Bap31, which causes rapid transmission of ER calcium signals to the mito-
chondria via the IP3 receptor. At close ER-mitochondria contact sites, mitochondria takes up calcium into the matrix via the mitochondrial
calcium channels MICU1 or LETM1. The massive influx of calcium leads to mitochondrial fission, cristae remodeling, and cytochrome c
release. Mfn2 is enriched in the mitochondria-associated membranes (MAM) of the endoplasmic reticulum (ER), where it interacts with
Mfn1 and Mfn2 on the mitochondria to form interorganellar bridges. Upon apoptosis signal, a BH3-only member of the Bcl-2 family,
Bik, induces Ca2+ release from the ER and, in turn, induces Drp1 recruitment to the mitochondria and their fragmentation and cristae
remodeling. SERCA, sarco/endoplasmic reticulum Ca2+ -ATPase. MICU1, mitochondrial calcium uptake 1. LETM1, leucine zipper/EF hand-
containing transmembrane 1.

can elicit mitochondrial apoptosis. ER targeting of Bik, a onstrated that hFis1 localized to the MAM transmits an
BH3-only member of the Bcl-2 family, induces Ca2+ release apoptosis signal from the ER to mitochondria by interacting
from the ER and its concomitant uptake by the mitochon- with Bap31 at the ER to form a platform for the recruitment
dria, which in turn induces Drp1 recruitment to the mito- of the initiator procaspase-8. Apoptotic signals induce cleav-
chondria and their fragmentation and cristae remodeling age of Bap31 into p20Bap31, which causes the rapid trans-
(Figure 3) [93]. Mammalian mitochondrial Fis1 is an ortho- mission of ER calcium to the mitochondria through inositol
log of yeast Fis1 thought to be involved in recruitment of triphosphate receptors at the ER-mitochondria junction
Drp1 to the mitochondria as in yeast [94]. Although recent [97]. Ca2+ influx into the mitochondria stimulates Drp1-
experiments revealed that Fis1 is not necessary for Drp1- dependent mitochondrial fission and cytochrome c release.
dependent mitochondrial fission in mammals [10, 24, 25], Thus, the hFis1-Bap31 complex, bridging the mitochondria
it might have another important role. In this context, over- and ER, functions as a platform to activate the initiator pro-
expression of hFis1 (for human Fis1) induces mitochondrial caspase in apoptosis signaling (Figure 3). Recently Green
fragmentation concomitant with Bax/Bak-dependent release and collaborators provided evidence that contacts between
of cytochrome c into the cytosol [95]. Of note, hFis1 does not mitochondria and other organelles such as ER are involved in
directly activate Bax and Bak, but induces ER Ca2+ -depend- regulation of the levels of sphingolipid metabolites that are
ent mitochondrial dysfunction, leading to mitochondrial required for Bax/Bak activation [98]. Distinct from the
apoptosis [96]. Interestingly, Iwasawa et al. recently dem- substrate or ion transfer function of the ER-mitochondria
International Journal of Cell Biology 7

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Acknowledgment ulate mitochondrial fusion and are essential for embryonic
development,” Journal of Cell Biology, vol. 160, no. 2, pp. 189–
This work has been supported by and Culture of Japan to 200, 2003.
Katsuyoshi Mihara and grants from the Ministry of Edu- [18] A. Santel and M. T. Fuller, “Control of mitochondrial mor-
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