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mit. are highly dynamic, ​constantly undergoing fission and fusion​. Fission results in the production
of short mit. rods or spheres. In contrast, fusion promotes a long, filamentous morphology of mit.
In healthy cells​, the ​frequencies​ ​of fusion and fission events are ​finely tuned and balanced​ to
maintain mit. homeostasis.
Mit fission & fusion ​-> function, inheritance, quality control
Under​ intracellular or extracellular ​stresses​, this ​balance is disrupted​, resulting in the cleavage of
mit. from an elongated network into small spheres or short rods, i.e., ​mit. fragmentation​.
fusion : Mfn1, Mfn2, and OPA1,
fission : Drp1 and Fis1.
Defects​ ​in these proteins​ lead to severely ​altered mit. morphology​ as well as ​impaired mit.
function​, ​loss of mit. DNA​ (mtDNA) ​integrity​, and ​eventually cell death
In mammals,
developmental defects
neurological anomalies
neurodegenerative diseases
l​ ​Mit. fission machinery
a large GTPase
essential role in mit. fission in mammalian cells
In unstressed cells​, Drp1 is mainly ​cytosolic​.
Upon stimulation, activated and translocates to the scission sites of MOM through interaction
with Fis1​,​ where they oligomerize and form spirals to constrict MOM through GTP hydrolysis,
resulting in mit. fission.
After fission, Drp1 ​returns to the cytosol
Activation, translocation
are regulated by mechanisms of ​posttranslational modifications​ including ​phosphorylation,
ubiquitylation, sumoylation
Blockade of Drp1 can suppress mit. fission, leading to elongated mit.; conversely, overexpression of
Drp1 results in mit. fragmentation
mammalian cells
small membrane protein
evenly anchored on MOM​ through a C-terminal ​transmembrane domain
N-terminal​ region facing the ​cytosol
The ​cytosolic domain facilitate specific protein–protein interactions.
Fis1 act as a ​receptor protein for Drp1​ on the outer membrane of mit.
Overexpression of Fis1 promoted mit. fission resulting in mit. fragmentation, followed by the release of
cytochrome c and ultimately apoptosis
transmembrane (TM) domain, which facilitate Fis1 anchoring on the outer mit. membrane (OMM).
l​ ​Mit. fusion machinery
Mfn1, Mfn2, OPA1
all large GTPases
Mfn1 and Mfn2​ are ​localized to the MOM​ ​OPA1 is localized​ ​MIM
Successful​ mit. fusion requires a ​coordinated action of Mfns and OPA1​, although it is ​unclear​ how
the molecular events at ​MOM are coordinated with those at MIM
fusion starts from the MOM fusion, followed by MIM fusion
contain GTPase domain, transmembrane (TM) domains, (HR1 and HR2).
HR2​ ​functions in mit. tethering.
interaction of adjacent HR2 regions-> mitofusin oligomerization(homodimers or heterodimers)
through GTP hydrolysis->MOM fusion
Mfn1 is the main tethering protein, whereas Mfn2 may have a regulatory role.
-maintenance of the cristae structure
-preservation of cytochrome c in mit.
-maintenance of mit. electron transport chain
-mtDNA stability
impaired mit. fusion links to severe defects in cell respiration in neurodegenerative disorders
cell injury and apoptosis->​ mit. fragmentation
combined result of the activation of fission and the suppression of fusion.
involvement of Bcl-2 family proteins, Drp1, and Ca2+/calcineurin-mediated dephosphorylation.
Reactive oxygen species (ROS) and mit. permeability transition (MPT)
​Bcl-2 family proteins
Characterized by the presence of Bcl-2 homology (BH) domain
(a) multi-BH domain/ antiapoptotic
Bcl-2 and Bcl-xL;
(b) multi-BH domain proapoptotic Bax and Bak
(c) BH3-only proteins(only one BH domain)
Bid and Bad
Bcl-2 family proteins are recognized as the ​central regulators​ of mit. integrity during cell injury and
Bax and Bak​ provide the requisite gateway of ​mit. outer membrane permeabilization​ (​MOMP​),
which is ​inhibited by Bcl-2/Bcl-xL​ under n
​ ormal conditions​ and ​activated by BH3-only proteins
during apoptosis​.
n​ ​In unstressed cells
interacts with both Mfn1/2
to maintain a filamentous mit. network
inactivated in the cytosol
n​ ​apoptotic stress,
dissociates from Mfn2
increases ​its association​ with Mfn1
à ​suppression of mit. fusion ​à mit. fragmentation
activated and translocates to mit.
Fragmented mit. are sensitized to​ Bax insertion ​and ​oligomerization​, leading to the formation of
pathological pores ​for the​ release of ​apoptogenic factors such as​ cytochrome c.
​Drp1 activation
posttranslational modifications​, including ​phosphorylation, dephosphorylation, ubiquitination,
sumoylation, and S-nitrosylation ​have been implicated in Drp1 regulation under various
physiological and pathological conditions
Thus, depending on the​ experimental condition, ​Drp1 may be​ phosphorylated at multiple sites ​by
different protein kinases, ​resulting in either ​inhibition or activation ​of mit. fission.
Ex) Ca2+/calmodulindependent protein kinase-a (CaMKI) activates mit. fission
Rho-associated coiled coil–containing protein kinase 1​ ​phosphorylates Drp1 under high-glucose
stimulation, resulting in Drp1 translocation and mit. fission.
dephosphorylation of Drp1 at Ser637 by calcineurin promotes Drp1 translocation to mit. and mit.
fragmentation, sensitizing cells to apoptosis.
n neurons, PKCd can phosphorylate Drp1 at Ser579 inducing mit. fragmentation to contribute to cell
death under oxidative stress.
, ubiquitination of Drp1 by MARCH5 resulting in mit. fission.73 Sumoylation of Drp1 induce mit.
fragmentation and apoptosis.
S-nitrosylation has been shown to increase Drp1 dimer formation and GTPase activity, leading to mit.
fission or fragmentation during nitric oxide–induced neuronal synaptic injury and death, suggesting a
novel pathogenic mechanism of neurodegeneration.
Perturbation of ​Ca2+ homeostasis​ has a ​crucial role in cell injury and death.​ Physiologically, ​mit.
are involved in ​the maintenance of Ca2+​ homeostasis ​by buffering cytosolic Ca2+ when it rises
to high levels.​ However, ​excessive Ca2+​ overload in mit. m
​ ay lead to mit. damage, resulting in
cell injury and death.
sustained ​Ca2+ rise in cytosol can induce mit. fragmentation ​in a Drp1-dependent manner.
a Ca2+-activated phosphatase
calcineurin may promote apoptosis ​through at least two distinct mechanisms,
1. Drp1
high cytosolic Ca2+ was shown to ​activate calcineurin​ to directly ​dephosphorylate Drp1​ at
Ser637,​ leading to ​Drp1 ​activation​ and translocation to the mit. to induce mit. ​fission and
2. ​dephosphorylation​ of the ​proapoptotic Bcl-2 family protein Bad
Reactive oxygen species
Mit. are known to be a major ​intracellular source of ROS​. Under ​pathological conditions,
uncoupling of oxidative phosphorylation​ and ​loss of mit. membrane integrity​ induce excessive
ROS production​ from the ​respiratory chain,​ especially at the ​Complex I and III.
In contrast, mit. are also a ​critical​ ​target of the damaging effects of ROS​. Oxidative damage leads
to ​mit. dysfunction and disruption​, triggering ​MPT​ and/or the release ​of proapoptotic proteins
like cytochrome c​ to induce cell death.
neurons exposed to oxidative stress an increased ROS production was shown to be accompanied by
mit. fragmentation and cell death
Thus, ​there is a complex interaction between ROS and mit. dynamics.
In some experimental models, ROS may be the triggering event for mit. fragmentation, but in
others mit. fragmentation may lead to mit. dysfunction and ROS production.
under certain conditions, these two events may exacerbate each other to form a ​vicious cycle
ultimately resulting in cell injury and death.
MTP (mit. 투과성 변화)
fragmentation ​has a​ crucial role ​in​ mit. injury ​during ​cell death, ​especially in the​ MOMP
how the fragmentation, a seemingly morphological change, contributes to MOMP and loss of mit.
‘two-hit’ hypothesis
Bak triggers the first hit​, ​mit. fragmentation,
second hit that involves ​Bax activation​ and formation of ​pathological pores in the MOM
fragmentation​ is likely process that​ facilitates Bax activation in mit. l membrane
it emphasizes on a ​collaborative action ​of Bak and Bax in promoting ​MOMP
preservation of​ filamentous mit.​ by either blocking mit. fission or enhancing mit. fusion can ​suppress
Bax insertion and oligomerization in mit. membrane.
Moreover, ​mitofusin-null cells​ with fragmented mit. are highly ​sensitive to Bax insertion​ and
oligomerization​ in mit. membrane resulting in increased ​MOMP and apoptosis
Together, these results suggest that the alteration of ​mit. dynamics and consequent mit.
fragmentation contribute to MOMP​ ​at least partially by facilitating Bax insertion and activation
in mit. membrane
- during apoptosis. Drp1​ contributes to​ MOMP Drp1 promotes Bax oligomerization​ by triggering
membrane tethering and hemifusion.
Importantly, during apoptosis associated mit. fragmentation, Drp1 may constrict the MOM resulting in
the formation of similar intermediate membrane structures to induce Bax oligomerization
Cristae remodeling
the release of apoptogenic factors​ from mit. also depends on the remodeling of mit. cristae, the
inner membrane structure
This is particularly true for ​cytochrome c​ because ​~85%​ of the molecule is sequestered ​within the
mit. cristae​ and as a result, ​its release requires the opening of the cristae.
(complete release of cytochrome c was induced by the combination of cristae remodeling, mit.
fragmentation, and Bax activation)
remodeling of mit. cristae
fusion of individual cristae ​& ​widening of cristae junctions ​resulting in the​ opening into the
intermembrane space ​for cytochrome c release
OPA1​ ​existed as both long and short forms which interacted and ​oligomerized to tighten the cristae
Downregulation of OPA1 or disruption of OPA1 oligomers not only caused mit. fragmentation but also
disrupted normal cristae structure
OPA1 may ​govern the remodeling of mit. cristae​ ​independently​ from its regulation of ​mit. fusion
has also been ​implicated​ in the remodeling and opening of mit. cristae
complete release of cytochrome c was induced by the combination of cristae remodeling, mit.
fragmentation, and Bax activation
inhibition of mit. Fission(Drp1) may block the release of soluble OPA1, which is required for
cristae remodeling and cytochrome c release from mit.
mit. fragmentation during apoptosis may affect cristae remodeling
cristae remodeling is a key event induced by mit. fragmentation for the release of apoptogenic factors,
such as cytochrome c.
the molecular basis linking these structural changes is largely unknown and deserves further in-depth
Respiration and ATP production
Thus, ​suppression of either fusion or fission results in mit. dysfunction, ​manifested by a
reduction in respiration and ATP production.
dynamic balance,​ and not fission or fusion alone, ​is important​ for the maintenance of ​mit. function
and long-term health.