MIT. DYNAMICS
developmental defects
neurological anomalies
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,
neurodegenerative diseases
 Mit. fission machinery
Fis1
Drp1
mammalian cells
a large GTPase
essential role in mit. fission in mammalian cells
small membrane protein
evenly anchored on MOM through a C-
In unstressed cells, Drp1 is mainly cytosolic.
Upon stimulation, activated and translocates
terminal transmembrane domain
N-terminal region facing the cytosol
to the scission sites of MOM through
interaction with Fis1, where they oligomerize
The
and form spirals to constrict MOM through
protein–protein interactions.
cytosolic
domain
facilitate
specific
GTP hydrolysis, resulting in mit. fission.
After fission, Drp1 returns to the cytosol
Fis1 act as a receptor protein for Drp1 on the
outer membrane of mit.
Activation, translocation
are
regulated
by
posttranslational
mechanisms
modifications
of
Overexpression of Fis1 promoted mit. fission
including
resulting in mit. fragmentation, followed by the
phosphorylation, ubiquitylation, sumoylation
release
of
cytochrome
c
and
ultimately
apoptosis
Blockade of Drp1 can suppress mit. fission,
leading
to
overexpression
fragmentation
elongated
of
Drp1
mit.;
results
conversely,
in
mit.
transmembrane (TM) domain, which facilitate
Fis1 anchoring on the outer mit. membrane
(OMM).
-mtDNA stability
 Mit. fusion machinery
Mfn1, Mfn2, OPA1
impaired mit. fusion links to severe defects in
all large GTPases
cell respiration in neurodegenerative disorders
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
Mfn1/2
contain GTPase domain, transmembrane (TM)
domains, (HR1 and HR2).
HR2 functions in mit. tethering.
interaction
mitofusin
of
adjacent
HR2
regions->
oligomerization(homodimers
heterodimers)
through
GTP
or
hydrolysis-
>MOM fusion
Mfn1 is the main tethering protein, whereas
Mfn2 may have a regulatory role.
OPA1
-maintenance of the cristae structure
-preservation of cytochrome c in mit.
-maintenance of mit. electron transport chain
MECHANISMS
LEADING
TO
MIT.
FRAGMENTATION IN CELL INJURY
cell
injury
and
apoptosis->
the central regulators of mit. integrity
during cell injury and death.
mit.
fragmentation
Bax and Bak provide the requisite
gateway of mit. outer membrane
combined result of the activation of
fission and the suppression of fusion.
permeabilization (MOMP), which is
inhibited
by
Bcl-2/Bcl-xL
under
normal conditions and activated by
BH3-only proteins during apoptosis.
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
 In unstressed cells
Drp1 activation
posttranslational
Bak
including
interacts with both Mfn1/2
to
maintain
a
filamentous
modifications,
phosphorylation,
dephosphorylation,
mit.
network
Bax
ubiquitination,
sumoylation, and S-nitrosylation have
been implicated in Drp1 regulation
under
various
physiological
and
pathological conditions
inactivated in the cytosol
Thus, depending on the experimental
 apoptotic stress,
Bak
dissociates from Mfn2
increases its association with Mfn1
condition,
Drp1
may
be
phosphorylated at multiple sites by
different protein kinases, resulting in
either inhibition or activation of mit.
fission.
 suppression of mit. fusion  mit.
fragmentation
Bax
Ex)
Ca2+/calmodulindependent
protein kinase-a (CaMKI) activates
mit. fission
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.
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
overload in mit. may lead to mit. damage,
to mit. and mit. fragmentation, sensitizing
resulting in cell injury and death.
cells to apoptosis.
sustained Ca2+ rise in cytosol can
induce mit. fragmentation in a Drp1-
n neurons, PKCd can phosphorylate Drp1
dependent manner.
at Ser579 inducing mit. fragmentation to
contribute to cell death under oxidative
Calcineurin
stress.
a Ca2+-activated phosphatase
, ubiquitination of Drp1 by MARCH5
calcineurin may promote apoptosis
resulting in mit. fission.73 Sumoylation of
through
Drp1
mechanisms,
induce
mit.
fragmentation
and
apoptosis.
Drp1 dimer formation and GTPase activity,
leading to mit. fission or fragmentation
nitric
least
two
distinct
1. Drp1
S-nitrosylation has been shown to increase
during
at
oxide–induced
neuronal
high cytosolic Ca2+ was shown to
activate
calcineurin
dephosphorylate
leading
to
to
Drp1
Drp1
at
directly
Ser637,
activation
and
synaptic injury and death, suggesting a
translocation to the mit. to induce mit.
novel
fission and fragmentation.
pathogenic
mechanism
of
neurodegeneration.
2.
dephosphorylation
of
the
proapoptotic Bcl-2 family protein Bad
Ca2+/calcineurin
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+
Reactive oxygen species
Mit. are known to be a major intracellular
source
of
conditions,
ROS.
Under
uncoupling
phosphorylation
and
pathological
of
loss
oxidative
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
fragmentation,
but
fragmentation
may
event
in
for
mit.
others
mit.
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.
MECHANISMS
WHEREBY
DYNAMICS
ITS
OR
MIT.
DISRUPTION
it emphasizes on a collaborative action
of Bak and Bax in promoting MOMP
CONTRIBUTES TO MIT. DAMAGE AND
CELL DEATH
preservation of filamentous mit. by
either
blocking
mit.
fission
or
enhancing mit. fusion can suppress
MTP (mit. 투과성 변화)
Bax insertion and oligomerization in
fragmentation has a crucial role in mit.
injury during cell death, especially in
mit. membrane.
the MOMP
Moreover, mitofusin-null cells with
fragmented mit. are highly sensitive to
how the fragmentation, a seemingly
morphological change, contributes to
MOMP and loss of mit. integrity
triggers
the
Together, these results suggest that 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
mit. membrane resulting in increased
MOMP and apoptosis
‘two-hit’ hypothesis
Bak
Bax insertion and oligomerization in
alteration
of
mit.
consequent
dynamics
mit.
and
fragmentation
contribute to MOMP at least partially
by
facilitating
Bax insertion
and
activation in mit. membrane
- during apoptosis. Drp1 contributes
to
MOMP
Drp1
oligomerization
promotes
by
Bax
triggering
membrane tethering and hemifusion.
Importantly,
during
apoptosis
fusion
of
individual
cristae
&
associated mit. fragmentation, Drp1
widening of cristae junctions resulting
may constrict the MOM resulting in the
in
formation
intermembrane space for cytochrome
of
similar
intermediate
membrane structures to induce Bax
the
opening
into
the
c release
oligomerization
OPA1 existed as both long and short
Cristae remodeling
forms
the release of apoptogenic factors
from
mit.
also
depends
on
the
which
interacted
and
oligomerized to tighten the cristae
junctions.
remodeling of mit. cristae, the inner
membrane structure
Downregulation of OPA1 or disruption
of OPA1 oligomers not only caused mit.
This is particularly true for cytochrome
c because ~85% of the molecule is
fragmentation
but
also
disrupted
normal cristae structure
sequestered within the mit. cristae and
as a result, its release requires the
opening of the cristae.
OPA1 may govern the remodeling of
mit. cristae independently from its
regulation of mit. fusion
(complete release of cytochrome c
was induced by the combination of
cristae
remodeling,
mit.
fragmentation, and Bax activation)
Drp1
has
also
been
implicated
in
the
remodeling and opening of mit. cristae
remodeling of mit. cristae
complete release of cytochrome c was
induced by the combination of cristae
remodeling, mit. fragmentation, and
manifested
Bax activation
respiration and ATP production.
inhibition of mit. Fission(Drp1) may
dynamic balance, and not fission or
block the release of soluble OPA1,
fusion alone, is important for the
which
maintenance of mit. function and
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
investigation.
Respiration and ATP production
Thus, suppression of either fusion or
fission results in mit. dysfunction,
by
long-term health.
a
reduction
in