Trends in Molecular Medicine
ReviewMitophagy: the latest problem for Parkinson's disease
Section snippets
Parkinson's disease
Parkinson's disease (PD) is one of the most common neurodegenerative disorders affecting 1% of the population over the age of 65 [1]. Clinically, PD is characterized mainly by motor manifestations such as bradykinesia, resting tremor, rigidity and postural instability [1]. One of the most salient neuropathological features of PD is the loss of the dopamine-containing neurons in the substantia nigra pars compacta (SNpc), which is responsible for the profound reduction of dopamine in the striatum
Mitophagy
As reminded by DiMauro and Schon [8], the story of mitochondria in eukaryotic cells is fascinating. Indeed, a billion years ago, aerobic bacteria colonized anaerobic eukaryotic cells. Through this symbiotic relationship, bacteria evolved into mitochondria and the host cells acquired the ability to metabolically use oxygen. By all accounts, it seems that eukaryotic cells have lived ‘happily ever after’ with mitochondria. For instance, each eukaryotic cell from multicellular organisms is
Familial forms of PD point to a relation between PD and mitophagy
PD commonly arises sporadically but, in some cases, the disease is inherited. PARK6/PINK1 is one of the gene products associated with familial PD 30, 31. This 581-amino acid polypeptide is a serine/threonine kinase with a high degree of homology to the Ca2+/calmodulin kinase family that localizes to mitochondria. Loss-of-function mutations in the gene encoding PARK2/Parkin (an E3 ubiquitin ligase) can cause an autosomal recessive form of familial PD 31, 32. Drosophila carrying pink1 mutations
Do PINK1 and Parkin modify each other?
Parkin translocation to mitochondria relies on PINK1 expression (Figure 1), and if wild type but not functionally deficient mutated PINK1 is overexpressed, Parkin can be recruited to mitochondria with normal ΔΨm 4, 5, 6, 37. The latter observation suggests that PINK1, probably through its kinase activity, is a key signaling molecule in mitophagy and that it operates downstream to the intramitochondrial molecular alterations provoked by the loss of ΔΨm. PD-linked loss-of-function mutations in
Signaling and regulation of PINK1 and Parkin
Although we are gaining insights into the PINK1/Parkin molecular pathway, several important outstanding questions remain (Figure 1). For instance, regarding PINK1 biology, we still do not know how the loss of ΔΨm engages PINK1 signaling or how PINK1 triggers Parkin recruitment. Some recent observations might help clarify these intriguing questions. In mitochondria with normal ΔΨm, PINK1, which has a short half-life, is present in low amounts 5, 37. However, a loss in ΔΨm is associated with an
Mitophagy and fusion/fission
In connection to one of the above issues, one might wonder whether PINK1/Parkin modulates mitophagy through the fusion/fission machinery. Indeed, it is reasonable to believe that the smaller the mitochondrion, the better it can be handled by the autophagy machinery. Consistent with this speculation are reports that knocking down the fission proteins DRP1 and FIS1 or overexpressing the fusion protein OPA1 reduces mitophagy 19, 36. By contrast, an excess of fission, driven by the overexpression
Emerging united pathogenic theme
The multiplicity of genetic defects giving rise to similar PD phenotypes has prompted researchers to consider the possibility that a common pathogenic cascade could underlie neurodegeneration in many if not all forms of familial PD. To date, however, there is no clear and compelling pathway unifying these different PD-linked mutant proteins. Only PINK1 and Parkin seem to converge functionally. In familial forms of PD, owing to mutations in either of these genes, impaired Parkin recruitment to
Concluding remarks
The identification and understanding of PD-related proteins are valuable for providing insight into the pathogenic mechanisms of this neurodegenerative disorder. Impairment in quality control autophagy (i.e. autophagy triggered to enforce intracellular quality control by eliminating toxic protein aggregates or damaged organelles) has emerged as a prominent new pathogenic mechanism. Whether the scenario proposed for PINK1/Parkin familial PD (Figure 1) can be extrapolated to sporadic PD remains
Acknowledgments
The authors are supported by NIH Grants AG021617, NS042269, NS062180, NS064191 and NS38370; US Department of Defense grants (W81XWH-08-1-0522, W81XWH-08-1-0465); the Parkinson Disease Foundation (New York, NY, USA); the Thomas Hartman Foundation For Parkinson's Research; and the MDA/Wings-over-Wall Street. S.P. is the Page and William Black Professor of Neurology.
References (85)
- et al.
Parkinson's disease: mechanisms and models
Neuron
(2003) PINK1 is recruited to mitochondria with parkin and associates with LC3 in mitophagy
FEBS Lett.
(2010)Selective degradation of mitochondria by mitophagy
Arch. Biochem. Biophys.
(2007)Mitochondria-anchored receptor Atg32 mediates degradation of mitochondria via selective autophagy
Dev. Cell
(2009)Atg32 is a mitochondrial protein that confers selectivity during mitophagy
Dev. Cell
(2009)Parkin stabilizes PINK1 through direct interaction
Biochem. Biophys. Res. Commun.
(2009)PINK1 controls mitochondrial localization of Parkin through direct phosphorylation
Biochem. Biophys. Res. Commun.
(2008)A role for ubiquitin in selective autophagy
Mol. Cell
(2009)p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy
J. Biol. Chem.
(2007)Nix is critical to two distinct phases of mitophagy: reactive oxygen species (ROS)-mediated autophagy induction and Parkin-ubiqutin-p62-mediated mitochondria priming
J. Biol. Chem.
(2010)
The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress
Cell
HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin
J. Biol. Chem.
Normal mitochondrial dynamics requires rhomboid-7 and affects Drosophila lifespan and neuronal function
Curr. Biol.
Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling
Cell
Bax/Bak-dependent release of DDP/TIMM8a promotes Drp1-mediated mitochondrial fission and mitoptosis during programmed cell death
Curr. Biol.
High levels of Fis1, a pro-fission mitochondrial protein, trigger autophagy
Biochim. Biophys. Acta
Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view
Biochim. Biophys. Acta
Autophagy is activated by apoptotic signalling in sympathetic neurons: An alternative mechanism of death execution
Mol. Cell Neurosci.
Mitochondria are selectively eliminated from eukaryotic cells after blockade of caspases during apoptosis
Curr. Biol.
Lewy bodies
Proc. Natl. Acad. Sci. U. S. A.
PINK1-dependent recruitment of Parkin to mitochondria in mitophagy
Proc. Natl. Acad. Sci. U. S. A
PINK1 Is selectively stabilized on impaired mitochondria to activate Parkin
PLoS Biol.
PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1
Nat. Cell Biol.
Mitochondrial respiratory-chain diseases
N. Engl. J. Med.
The mitochondrial gateway to cell death
IUBMB Life
Functions and dysfunctions of mitochondrial dynamics
Nat. Rev. Mol. Cell Biol.
Axonal mitochondrial transport and potential are correlated
J. Cell Sci.
Mitochondrial dynamics in mammalian health and disease
Physiol. Rev.
Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A
Nat. Genet.
eOPA1: an online database for OPA1 mutations
Hum. Mutat.
High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease
Nat. Genet.
‘Rejuvenation’ protects neurons in mouse models of Parkinson's disease
Nature
Tracker dyes to probe mitochondrial autophagy (mitophagy) in rat hepatocytes
Autophagy
Fission and selective fusion govern mitochondrial segregation and elimination by autophagy
EMBO J.
The molecular mechanism of mitochondria autophagy in yeast
Mol. Microbiol.
Eaten alive: a history of macroautophagy
Nat. Cell Biol.
Atg11 links cargo to the vesicle-forming machinery in the cytoplasm to vacuole targeting pathway
Mol. Biol. Cell
Role of BNIP3 and NIX in cell death, autophagy, and mitophagy
Cell Death Differ.
Selective mitochondrial autophagy during erythroid maturation
Autophagy
NIX induces mitochondrial autophagy in reticulocytes
Autophagy
Essential role for Nix in autophagic maturation of erythroid cells
Nature
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