Download Mitochondrial quality control by the ubiquitin

8th International Meeting on Yeast Apoptosis
Mitochondrial quality control by the
ubiquitin–proteasome system
Eric B. Taylor and Jared Rutter1
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84199, U.S.A.
Biochemical Society Transactions
www.biochemsoctrans.org
Abstract
Mitochondria perform multiple functions critical to the maintenance of cellular homoeostasis and their
dysfunction leads to disease. Several lines of evidence suggest the presence of a MAD (mitochondriaassociated degradation) pathway that regulates mitochondrial protein quality control. Internal mitochondrial
proteins may be retrotranslocated to the OMM (outer mitochondrial membrane), multiple E3 ubiquitin ligases
reside at the OMM and inhibition of the proteasome causes accumulation of ubiquitinated proteins at the
OMM. Reminiscent of ERAD [ER (endoplasmic reticulum)-associated degradation], Cdc48 (cell division cycle
42)/p97 is recruited to stressed mitochondria, extracts ubiquitinated proteins from the OMM and presents
ubiquitinated proteins to the proteasome for degradation. Recent research has provided mechanistic insights
into the interaction of the UPS (ubiquitin–proteasome system) with the OMM. In yeast, Vms1 [VCP (valosincontaining protein) (p97)/Cdc48-associated mitochondrial-stress-responsive 1] protein recruits Cdc48/p97
to the OMM. In mammalian systems, the E3 ubiquitin ligase parkin regulates the recruitment of
Cdc48/p97 to mitochondria, subsequent mitochondrial protein degradation and mitochondrial autophagy.
Disruption of the Vms1 or parkin systems results in the hyper-accumulation of ubiquitinated proteins at
mitochondria and subsequent mitochondrial dysfunction. The emerging MAD pathway is important for the
maintenance of cellular and therefore organismal viability.
Introduction
Mitochondria perform many critical functions in eukaryotes.
Among these, mitochondria sustain cells with a continuous
supply of ATP, integrate biosynthetic pathways, co-ordinate
redox signalling and regulate apoptotic balance. Because of
the multiple critical processes mitochondria facilitate, their
dysfunction leads to the loss of cellular function and, in
multicellular organisms, the onset of disease. In humans,
mitochondrial dysfunction causes numerous pathologies
including cancer [1,2], heart failure [3], neurological diseases
[4], myopathies [5] and a multitude of other familial disorders.
Although the molecular bases for mitochondrial dysfunction are poorly understood and probably diverse, damage by
ROS (reactive oxygen species) is thought to be a primary
cause. Because mitochondria house the reactions of the
electron transport chain and are a final destination for
molecular oxygen, they are the major cellular source of ROS.
During oxidative phosphorylation, electrons may escape the
electron transport chain and react with molecular oxygen
to form the highly reactive superoxide anion, which can
form other highly reactive ROS and reactive nitrogen species.
Although mitochondria are equipped with mechanisms
Key words: cell division cycle 48 (Cdc48), mitochondrion, p97, parkin, ubiquitin–proteasome
system, VCP (p97)/Cdc48-associated mitochondrial-stress-responsive 1 (Vms1).
Abbreviations used: AAA, ATPase associated with various cellular activities; ERAD, ER
(endoplasmic reticulum)-associated degradation; IMM, inner mitochondrial membrane; MAD,
mitochondria-associated degradation; mtDNA, mitochondrial DNA; OMM, outer mitochondrial
membrane; ROS, reactive oxygen species; SOD1, superoxide dismutase 1; mSOD1, mutant SOD1;
UCP2, uncoupling protein 2; UPS, ubiquitin–proteasome system; Vms1, VCP (valosin-containing
protein) (p97)/Cdc48-associated mitochondrial-stress-responsive 1.
1
To whom correspondence should be addressed (email [email protected]).
Biochem. Soc. Trans. (2011) 39, 1509–1513; doi:10.1042/BST0391509
to quench free radicals and minimize oxidative damage
to component proteins and lipids, these systems are not
sufficient for eliminating damage.
Mitochondria are further subjected to unique biochemical
stresses because of their complex biogenesis. Mitochondrial
biogenesis requires the co-ordinated assembly and sorting
of both nuclear- and mitochondrially encoded proteins.
The double membrane structure of mitochondria results
in several distinct mitochondrial compartments, the matrix,
the inner membrane, the intermembrane space and the
outer membrane. Nuclear-encoded mitochondrial proteins
must be translocated from the cytosol and sorted to one
of these compartments. After sorting, they must often be
co-ordinately assembled into multiprotein complexes with
mitochondrially encoded proteins and cofactors. Although
these processes are tightly regulated by dedicated translocases
and chaperone proteins, import, sorting and assembly may
fail.
Thus mitochondria are subjected to unique and sometimes
overwhelming biochemical stresses, resulting from both their
function as a containment vessel for oxidative phosphorylation and from their unique biogenic requirements. The
acute failure of ROS detoxifying and protein sorting and
assembly systems may initiate progressive mitochondrial
failure. ROS generation increases with mitochondrial defects.
Therefore mitochondrial dysfunction can spiral into a vicious
cycle whereby damaged mitochondria produce more reactive
ROS that further damage mitochondria and disrupt protein
homoeostasis, leading to more ROS and so on [6]. If
mitochondria continuously sustain damage, how do they
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escape the progressive accumulation of damage until complete
failure?
Mitochondrial quality control
Elaborate quality control mechanisms have evolved for
protecting mitochondria from ROS and repairing or eliminating damaged mitochondria. These mechanisms include
autophagic consumption of dysfunctional mitochondria [7],
constant fusion and fission to partition and dissipate damaged
mitochondria and mitochondrial proteolytic systems to
degrade damaged mitochondrial proteins. Proteases for
mitochondrial protein quality control are found within each
mitochondrial compartment. Two AAA + proteases (AAA
is ATPase associated with various cellular activities), Lon and
ClpXP, reside in the matrix and degrade oxidatively damaged
proteins in the matrix. A pair of AAA metalloproteases
patrols opposite faces of the mitochondrial inner membrane.
The m-AAA (matrix AAA) protease faces and performs
protein quality control functions on the matrix side, while
the i-AAA (intermembrane AAA) protease does the same
at the intermembrane space side [8,9]. These proteases
are important for clearing dysfunctional proteins from the
inner membrane, which may accumulate due to failures in
respiratory chain complex assembly or oxidative damage.
Although the mitochondrial proteases collectively are critical
for the prevention of mitochondrial dysfunction, their study
has failed to explain aspects of mitochondrial quality control,
particularly the degradation of outer membrane proteins.
The UPS (ubiquitin–proteasome system)
and ERAD [ER (endoplasmic reticulum)associated degradation]
Because the OMM (outer mitochondrial membrane) is
contiguous with the cytosol, it may be accessed by cytosolic
proteolytic systems, such as the UPS [10–12]. Most targeted
cellular protein degradation is carried out by the UPS.
For targeting to the proteasome, damaged proteins are
covalently tagged on lysine residues with the small protein
modifier ubiquitin, which itself may be tagged to form
polyubiquitin chains. Ubiquitin-binding proteins recognize
and present ubiquitinated proteins to the proteasome, where
they are degraded. Marking a protein for degradation by
ubiquitination requires the co-ordinated action of three
classes of enzymes. E1 enzymes activate ubiquitin by
adenylation, E2 enzymes conjugate activated ubiquitin and
E3 enzymes provide selectivity to the UPS by transferring
E2-conjugated ubiquitin to specific substrates. Among its
many roles, the UPS performs critical protein quality control
functions at the ER, the central cellular hub for protein sorting
and secretion.
Because the UPS is excluded from the ER lumen by
the ER membrane, a system called ERAD has evolved
for retrotranslocating proteins from the ER lumen for
degradation by the UPS. Partially retrotranslocated proteins
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Authors Journal compilation are ubiquitinated by several E3 ubiquitin ligases that reside
at the ER membrane. After being marked for degradation by
ubiquitination, these proteins must be fully extracted from
the ER membrane. The mechanism for this extraction is
conserved throughout eukarya. During ER stress, the AAA
ATPase Cdc48 (cell division cycle 42)/p97, in complex with
its adaptor proteins Npl4 and Ufd1, is recruited to the
ER, extracts ubiquitinated proteins and presents them to
the proteasome, which degrades them [13]. Thus the UPS
regulates protein quality control at the ER, an organelle that
excludes it.
MAD (mitochondria-associated
degradation)
Because the UPS is similarly excluded from mitochondria,
an ERAD-like system, MAD, has been proposed to
operate at mitochondria [10–12,14,15]. In this system, matrix
or inner membrane proteins are retrotranslocated to the
outer membrane for ubiquitination and targeting to the
proteasome. Several observations support the existence of
such a system. Proteins associated with various mitochondrial
compartments are ubiquitinated and subjected to proteasomal degradation, but without a mechanistic explanation
this could be discounted as being pre-import regulation. If an
ERAD-like system operates at the OMM, then by analogy,
the OMM, like the ER membrane, should also harbour E3
ubiquitin ligases. Indeed, several E3 ligases reside at the
OMM. Current data suggest that they may perform both
regulatory and protein quality control functions.
Mitol/March5 ubiquitinates Drp1 and Fis1, two proteins regulating mitochondrial fission [16]. Depletion
of Mitol/March5 results in excess fission, leading to
mitochondrial fragmentation. In a non-regulatory role,
Mitol/March5 also ubiquitinates the mSOD1 [mutant SOD1
(superoxide dismutase 1)] that causes amyotrophic lateral
sclerosis, and which accumulates in mitochondria [17].
Mitol/March5 depletion causes increased mitochondrial
mSOD1 accumulation, suggesting that ubiquitination of
mSOD1 at mitochondria is important for its degradation,
thereby implicating the UPS at mitochondria. Additional
mitochondrial E3 ligases include Mulan, Mdm30, Mfb1 and
Rsp5, which all induce changes in mitochondrial morphology
on knockdown or deletion [11]. Mdm30 ubiquitinates Fzo1,
which is important for mitochondrial fusion in budding yeast
[18], but targets for the other ligases have not been discovered.
A recent proteomics study identified over 100 ubiquitinated
proteins in mitochondrial extracts purified from mouse heart,
providing numerous putative targets for known and yet-tobe-discovered mitochondrial E3 ligases [19].
Until recently, there was no mechanistic evidence for
MAD. However, data from Margineantu et al. [20]
demonstrate that proteins are ubiquitinated at mitochondria,
and some proteins may be retrotranslocated to the OMM to
be accessed by the proteasome. They found that the OSCP
(oligomycin-sensitivity-conferring protein) subunit of the
8th International Meeting on Yeast Apoptosis
F1 Fo -ATPase, which resides at the IMM (inner mitochondrial
membrane), is retrotranslocated to the OMM where it
is ubiquitinated and degraded by the proteasome. More
broadly, treatment with proteasome inhibitors increased the
accumulation of many mitochondrial proteins, including
the mitochondrially encoded COX1 (cyclo-oxygenase 1),
which because of its synthesis in the matrix would require
retrotranslocation for access by the proteasome. Treatment
with lysosomal and macroautophagy inhibitors has no
such effect, suggesting that the increase in mitochondrial
proteins did not result from a regulatory interaction between
proteasomal inhibition and mitophagy. Consistent with this
proposed phenomenon, Azzu et al. [21,22] found that UCP2
(uncoupling protein 2) and UCP3, which also reside at the
IMM, are degraded by the proteasome. They constructed
reconstituted systems in vitro, where UCP2 and UCP3
in intact, energized mitochondria are degraded by the
proteasome, implying retrotranslocation. However, despite
evidence for retrotranslocation to the OMM, a mechanism
for the interaction between the UPS and the OMM remained
undefined.
Vms1 regulates mitochondrial protein
degradation
We recently identified a mechanism in yeast whereby a
novel protein, which we have named Vms1 [VCP (valosincontaining protein) (p97)/Cdc48-associated mitochondrialstress-responsive 1], recruits Cdc48/p97 and Npl4 to stressed
mitochondria [15]. Under normal growth conditions the
Vms1 complex resides in the cytosol. However, on treatment
with mitochondrial toxicants including uncouplers, respiratory chain poisons and oxidants, Vms1 recruits Cdc48/97 and
Npl4 to mitochondria, reminiscent of the Cdc48/p97–Npl4–
Ufd1 complex that is recruited to the ER during ERAD and
extracts ubiquitinated proteins for proteasomal degradation.
If the Vms1 complex performs such a role at mitochondria as
part of MAD, then its deletion should cause the accumulation
of ubiquitinated proteins at mitochondria.
Indeed, deletion of VMS1 caused an increase in polyubiquitinated mitochondrial proteins and further experiments
demonstrated that VMS1 deletion decreased the rate of Fzo1
degradation, a known substrate of the mitochondrial E3 ligase
Mdm30 [15]. Efforts are under way to identify additional
substrates of the Vms1/MAD system. Tran et al. [23] recently
found Vms1 to generally regulate ubiquitin unloading from
Cdc48/p97, a function that would be important during MAD,
but may also implicate Vms1 in some aspects of ERAD.
Biochemically, the Vms1 system appears to be an arm of
the UPS distinct from ERAD. By co-immunoprecipitation
experiments we found that the association of Vms1 and
Ufd1 with Cdc48/p97 is mutually exclusive, suggesting that
the Ufd1–Npl4–Cdc48/p97 complex is devoted to ERAD,
while the Vms1–Npl4–Cdc48/p97 complex is devoted to
MAD. Yet, Cdc48 translocation to mitochondria is not
absolutely dependent on Vms1. We observed translocation of
a reduced fraction of Cdc48 to mitochondria in the absence
of Vms1, indicating that there is at least one other mode for
targeting Cdc48 to mitochondria. However, under conditions
of mitochondrial stress that cause translocation of the Vms1
complex to mitochondria, the absence of Vms1 causes
mitochondrial accumulation of polyubiquitinated proteins,
biochemical defects and respiratory failure. Thus, in yeast,
Vms1-dependent MAD is critical for cell viability during
mitochondrial stress.
The Vms1 gene is highly conserved from yeast to
humans and initial data suggest that the Vms1 system
may be conserved throughout eukarya. We found that
Vms1 knockdown in Caenorhabditis elegans resulted in
hypersensitivity to H2 O2 , which caused Vms1 to translocate
to mitochondria [15]. Thus, as in yeast, Vms1 in C. elegans
is critical, at mitochondria, for cellular and organismal
viability under conditions of mitochondrial stress. Initial
data suggest that the conservation of the Vms1 system also
extends to mammalia. Human Vms1 partially rescues the
yeast VMS1 deletion phenotype and Vms1 in mammalian cells
also tandem-affinity purifies with Cdc48/p97. Thus Vms1
functions as a Cdc48/p97 adaptor protein in mammalian
systems. While the cellular function of Vms1 in mammals
remains to be elucidated, two recent studies have implicated
Cdc48/p97, and by analogy to yeast, Vms1, in OMM protein
degradation in mammalian systems, thereby providing
mechanistic insights into mammalian MAD.
p97 and parkin are recruited to
mitochondria
Xu et al. [24] found that the degradation of OMM proteins
Mfn1 and Mcl1 in mammalian cells is proteasome- and p97dependent. They also found a partial association of p97 with
mitochondria, indicating that a fraction of p97 associates
with mitochondria to regulate the turnover of OMM proteins
in mammalian systems. These findings were extended by
Tanaka et al. [25], who also reported that p97 localizes to
mitochondria, but with the additional finding that chemically
uncoupling mitochondria causes large-scale translocation
of p97 to mitochondria. This result is consistent with our
studies on Vms1 in yeast, where uncoupling causes the
recruitment of Cdc48/p97 to mitochondria by Vms1. They
also found that uncoupling-stimulated p97 translocation to
the OMM is dependent on the E3 ubiquitin ligase activity of
the protein parkin, which has no orthologues in yeast. This
finding provides a mechanistic link between Parkinson’s
disease and mitochondrial dysfunction.
Mutations in parkin are a major cause of familial
Parkinson’s disease, accounting for over 50% of all juvenileonset cases [26], and Parkinson’s disease has been increasingly
associated with mitochondrial dysfunction. Parkin is selectively recruited to depolarized mitochondria and marks them
for mitophagy [27], a topic only superficially addressed in this
review. Tanaka et al. [25] showed that uncoupling-stimulated,
parkin-dependent, p97 OMM localization facilitates the
proteasome-dependent degradation of Mfn1 and Mfn2,
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which prevents re-fusion of depolarized mitochondria.
Thus parkin acts upstream of recruitment of p97, and
potentially Vms1, to the OMM to enable the selective
mitophagy of depolarized mitochondria. Indeed, constitutive
overexpression of parkin in heteroplasmic cybrid cell
lines increases the ratio of wild-type to mutant mtDNA
(mitochondrial DNA), probably by increasing the mitophagy
of the defective mitochondria harbouring mutant mtDNA
[28]. In addition to its role in mitophagy, the parkin–p97
pathway exerts a general protein quality control function
at the OMM. Both Chan et al. [29] and Yoshii et al. [30]
recently demonstrated that mitochondrial uncoupling causes
the parkin-dependent degradation of multiple OMM proteins
independent of mitophagy. This is an important distinction
because it shows that the UPS broadly regulates OMM
protein degradation, a feature required of a bona fide ERADlike MAD system and provides a partial explanation of the
mechanism, further elucidating the MAD pathway.
Figure 1 Mitochondria-associated degradation
The UPS regulates protein degradation at the OMM. Some proteins in
other compartments may be retrotranslocated to the OMM. E3 ubiquitin
ligases at the OMM mark proteins, including those damaged by oxidative
stress, for degradation by ubiquitination. Cdc48/p97 is recruited to
extract ubiquitinated proteins and present them to the proteasome,
which degrades them. In mammalian systems, parkin is selectively
recruited to depolarized mitochondria and ubiquitinates proteins at the
OMM, and Cdc48/p97 is recruited in a parkin-dependent manner. In
yeast, Vms1 recruits Cdc48/p97 to stressed mitochondria, although a
fraction of Cdc48/p97 is recruited by an unidentified Vms1-independent
mechanism. The Vms1 gene is highly conserved in mammalian systems,
where its role in mitochondrial protein degradation remains to be
determined.
Summary and perspectives
Mitochondria are subject to unique stresses because they
house oxidative phosphorylation, originate from two genomes and have two membranes. To maintain mitochondrial
quality, a MAD pathway has been proposed to link
mitochondrial protein quality control with the UPS. Findings
from multiple groups have contributed to the delineation
of a MAD pathway that targets proteins at the OMM
or those retrotranslocated to it. Damaged proteins at the
OMM are ubiquitinated by resident or selectively recruited
E3 ligases, such as parkin in mammalian systems. Once
ubiquitinated, they are extracted by Cdc48/p97, presented
to the proteasome and degraded. However, despite recent
advances, some aspects of MAD remain superficially defined
and trigger many interesting questions.
Although several studies have demonstrated that OMM
proteins are ubiquitinated and degraded by the UPS
(Figure 1), direct evidence for retrotranslocation is limited.
To confirm retrotranslocation and to show that the UPS regulates protein quality for mitochondrial compartments other
than the OMM in a true ERAD-like manner, a mechanism
for retrotranslocation must be defined. Mechanistic details
are also lacking for the mode by which the UPS is recruited
to the OMM. In yeast, we demonstrated that Vms1 recruits
Cdc48/p97 to stressed mitochondria, but the molecular
steps regulating this translocation and the identity of the
mitochondrial receptor still require definition. In mammalian
systems, parkin recruitment to the OMM requires the
stabilization and activity of PINK1 [31], but the molecular
mechanism guiding parkin translocation has not been
described. The requisite steps between parkin recruitment
and large-scale UPS activation at the OMM also remain
undefined. However, despite answered questions, multiple
pieces of evidence support a general MAD model. Many
interesting discoveries that would unveil the mechanisms of
MAD are awaited.
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Authors Journal compilation Funding
We acknowledge the National Institutes of Health for the support
of our research on Vms1 and mitochondrial protein quality control.
Related research in the Rutter laboratory was supported by the
National Institutes of Health [grant numbers RO1GM087346 (to J.R.)
and K99AR059190 (to E.B.T.)].
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Received 15 June 2011
doi:10.1042/BST0391509
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