Top

Current Neurology and Neuroscience Reports

Published in:

01-06-2011

Molecular Mechanisms of PINK1-Related Neurodegeneration

Authors: Joe H. Pogson, Rachael M. Ivatt, Alexander J. Whitworth

Published in: Current Neurology and Neuroscience Reports | Issue 3/2011

Abstract

PINK1 is a mitochondrially targeted kinase that has been linked to a rare monogenic form of Parkinson’s disease (PD), a common neurodegenerative disease characterized by the degeneration of selected dopaminergic neurons. Intensive research using many model systems has clearly established a fundamental role for PINK1 in preventing mitochondrial dysfunction—a key mechanism long thought to play a central role in PD pathogenesis. Current hypotheses propose PINK1’s important functions involve mitophagy, mitochondrial calcium buffering, and mitochondrial quality control. Furthermore, recent findings have revealed that PINK1’s functions are likely regulated by a complex mechanism that includes regulated mitochondrial import and intramembrane proteolysis to influence its sub cellular and sub mitochondrial distribution. This review aims to summarize and evaluate recent findings, with particular emphasis on PINK1 localization, cleavage, and function in mitochondrial homeostasis.

Valente EM, Abou-Sleiman PM, Caputo V, et al. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science. 2004;304(5674):1158–60.PubMedCrossRef

Hardy J. Genetic analysis of pathways to Parkinson disease. Neuron. 2010;68(2):201–6.PubMedCrossRef

Abou-Sleiman PM, Muqit MMK, Wood NW. Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nat Rev Neurosci. 2006;7(3):207–19.PubMedCrossRef

Silvestri L, Caputo V, Bellacchio E, et al. Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Hum Mol Genet. 2005;14(22):3477–92.PubMedCrossRef

Sim CH, Lio DSS, Mok SS, et al. C-terminal truncation and Parkinson’s disease-associated mutations down-regulate the protein serine/threonine kinase activity of PTEN-induced kinase-1. Hum Mol Genet. 2006;15(21):3251–62.PubMedCrossRef

Deas E, Plun-Favreau H, Wood NW. PINK1 function in health and disease. EMBO Mol Med. 2009;1(3):152–65.PubMedCrossRef

Beilina A, Van Der Brug M, Ahmad R, et al. Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. Proc Natl Acad Sci USA. 2005;102(16):5703–8.PubMedCrossRef

Lin W, Kang UJ. Characterization of PINK1 processing, stability, and sub cellular localization. J Neurochem. 2008;106(1):464–74.PubMedCrossRef

•• Narendra DP, Jin SM, Tanaka A, et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 2010; 8(1): e1000298. This article provided compelling evidence for the dynamic nature of PINK1 stability leading to the conclusion that PINK1 is normally rapidly turned over in healthy mitochondria but becomes stabilized on dysfunctional mitochondria as a prelude to Parkin-induced mitophagy.PubMedCrossRef

10.

•• Matsuda N, Sato S, Shiba K, et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J. Cell Biol. 2010; 189(2): 211–221. This article provided compelling evidence for the dynamic nature of PINK1 stability leading to the conclusion that PINK1 is normally rapidly turned over in healthy mitochondria but becomes stabilized on dysfunctional mitochondria as a prelude to Parkin-induced mitophagy.PubMedCrossRef

11.

• Haque ME, Thomas KJ, D'Souza C, et al. Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP. Proc. Natl. Acad. Sci. U.S.A. 2008; 105(5): 1716–1721. This article provided the first evidence that at least part of PINK1’s neuroprotective function is within the cytoplasm. The full nature of this is not yet known.PubMedCrossRef

12.

•• Whitworth AJ, Lee JR, Ho VM, et al. Rhomboid-7 and HtrA2/Omi act in a common pathway with the Parkinson’s disease factors Pink1 and Parkin. Dis Model Mech 2008; 1(2–3): 168–174; discussion 173. This article provides important insight into how PINK1 is regulated by proteolysis. PINK1 undergoes an unusual intramembrane proteolytic processing by rhomboid-7/PARL. This was first shown genetically and biochemically in Drosophila and subsequently verified and extended in mammalian systems.PubMedCrossRef

13.

•• Jin SM, Lazarou M, Wang C, et al. Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J. Cell Biol. 2010; 191(5): 933–942. This article provides important insight into how PINK1 is regulated by proteolysis. PINK1 undergoes an unusual intramembrane proteolytic processing by rhomboid-7/PARL. This was first shown genetically and biochemically in Drosophila and subsequently verified and extended in mammalian systems. PubMedCrossRef

14.

•• Deas E, Plun-Favreau H, Gandhi S, et al. PINK1 Cleavage at position A103 by the mitochondrial protease PARL. Hum. Mol. Genet. 2010. Dec 6 [Epub ahead of print]. This article provides important insight into how PINK1 is regulated by proteolysis. PINK1 undergoes an unusual intramembrane proteolytic processing by rhomboid-7/PARL. This was first shown genetically and biochemically in Drosophila and subsequently verified and extended in mammalian systems.

15.

• Zhou C, Huang Y, Shao Y, et al. The kinase domain of mitochondrial PINK1 faces the cytoplasm. Proc. Natl. Acad. Sci. U.S.A. 2008; 105(33): 12022–12027. This article provided compelling evidence that PINK1 is mitochondrially targeted but extrudes to the outer surface, concurring with Haque et al. [11•] that an important site of action is within the cytoplasm. PubMedCrossRef

16.

Pridgeon JW, Olzmann JA, Chin L, Li L. PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol. 2007;5(7):e172.PubMedCrossRef

17.

• Weihofen A, Thomas KJ, Ostaszewski BL, et al. Pink1 forms a multiprotein complex with Miro and Milton, linking Pink1 function to mitochondrial trafficking. Biochemistry. 2009; 48(9): 2045–2052. This article provides an intriguing link to mitochondrial dynamics, which may directly or indirectly impact on mitochondrial transport, fission/fusion, clustering, and mitophagy, although the findings await verification. PubMedCrossRef

18.

Plun-Favreau H, Klupsch K, Moisoi N, et al. The mitochondrial protease HtrA2 is regulated by Parkinson’s disease-associated kinase PINK1. Nat Cell Biol. 2007;9(11):1243–52.PubMedCrossRef

19.

Clark IE, Dodson MW, Jiang C, et al. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature. 2006;441(7097):1162–6.PubMedCrossRef

20.

Park J, Lee SB, Lee S, et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature. 2006;441(7097):1157–61.PubMedCrossRef

21.

Kitada T, Pisani A, Porter DR, et al. Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci USA. 2007;104(27):11441–6.PubMedCrossRef

22.

Gautier CA, Kitada T, Shen J. Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc Natl Acad Sci USA. 2008;105(32):11364–9.PubMedCrossRef

23.

Gispert S, Ricciardi F, Kurz A, et al. Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. PLoS ONE. 2009;4(6):e5777.PubMedCrossRef

24.

Sämann J, Hegermann J, von Gromoff E, et al. Caenorhabditits elegans LRK-1 and PINK-1 act antagonistically in stress response and neurite outgrowth. J Biol Chem. 2009;284(24):16482–91.PubMedCrossRef

25.

Bandmann O, Flinn L, Mortiboys H. POMD08 zebrafish models for early onset Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2010;81(11):e59.CrossRef

26.

Greene JC, Whitworth AJ, Kuo I, et al. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci USA. 2003;100(7):4078–83.PubMedCrossRef

27.

Poole AC, Thomas RE, Andrews LA, et al. The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci USA. 2008;105(5):1638–43.PubMedCrossRef

28.

Exner N, Treske B, Paquet D, et al. Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin. J Neurosci. 2007;27(45):12413–8.PubMedCrossRef

29.

Yang Y, Ouyang Y, Yang L, et al. Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc Natl Acad Sci USA. 2008;105(19):7070–5.PubMedCrossRef

30.

Ziviani E, Tao RN, Whitworth AJ. Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc Natl Acad Sci USA. 2010;107(11):5018–23.PubMedCrossRef

31.

Wood-Kaczmar A, Gandhi S, Yao Z, et al. PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons. PLoS ONE. 2008;3(6):e2455.PubMedCrossRef

32.

Dagda RK, Cherra SJ, Kulich SM, et al. Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J Biol Chem. 2009;284(20):13843–55.PubMedCrossRef

33.

Mortiboys H, Thomas KJ, Koopman WJH, et al. Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Ann Neurol. 2008;64(5):555–65.PubMedCrossRef

34.

Morais VA, Verstreken P, Roethig A, et al. Parkinson’s disease mutations in PINK1 result in decreased complex I activity and deficient synaptic function. EMBO Mol Med. 2009;1(2):99–111.PubMedCrossRef

35.

Wang X, Schwarz TL. The mechanism of Ca2+ -dependent regulation of kinesin-mediated mitochondrial motility. Cell. 2009;136(1):163–74.PubMedCrossRef

36.

Twig G, Elorza A, Molina AJA, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 2008;27(2):433–46.PubMedCrossRef

37.

Narendra D, Tanaka A, Suen D, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol. 2008;183(5):795–803.PubMedCrossRef

38.

•• Vives-Bauza C, Zhou C, Huang Y, et al. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc. Natl. Acad. Sci. U.S.A. 2010; 107(1): 378–383. This paper provided the first evidence that PINK1 is required for Parkin translocation to dysfunctional mitochondria to promote mitophagy. PubMedCrossRef

39.

Michiorri S, Gelmetti V, Giarda E, et al. The Parkinson-associated protein PINK1 interacts with Beclin1 and promotes autophagy. Cell Death Differ. 2010;17(6):962–74.PubMedCrossRef

40.

Poole AC, Thomas RE, Yu S, et al. The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/parkin pathway. PLoS ONE. 2010;5(4):e10054.PubMedCrossRef

41.

Gegg ME, Cooper JM, Chau K, et al. Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet. 2010;19(24):4861–70. Epub 2010 Sep 24.PubMedCrossRef

42.

Geisler S, Holmström KM, Skujat D, et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol. 2010;12(2):119–31.PubMedCrossRef

43.

Narendra DP, Kane LA, Hauser DN, et al. p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy. 2010; 6(8)

44.

Misko A, Jiang S, Wegorzewska I, et al. Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex. J Neurosci. 2010;30(12):4232–40.PubMedCrossRef

45.

Hoepken H, Gispert S, Morales B, et al. Mitochondrial dysfunction, per oxidation damage and changes in glutathione metabolism in PARK6. Neurobiol Dis. 2007;25(2):401–11.PubMedCrossRef

46.

Piccoli C, Ripoli M, Quarato G, et al. Coexistence of mutations in PINK1 and mitochondrial DNA in early onset parkinsonism. J Med Genet. 2008;45(9):596–602.PubMedCrossRef

47.

Bender A, Krishnan KJ, Morris CM, et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet. 2006;38(5):515–7.PubMedCrossRef

48.

Gandhi S, Wood-Kaczmar A, Yao Z, et al. PINK1-associated Parkinson’s disease is caused by neuronal vulnerability to calcium-induced cell death. Mol Cell. 2009;33(5):627–38.PubMedCrossRef

49.

de Brito OM, Scorrano L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature. 2008;456(7222):605–10.PubMedCrossRef

50.

Surmeier DJ, Guzman JN, Sanchez-Padilla J. Calcium, cellular aging, and selective neuronal vulnerability in Parkinson’s disease. Cell Calcium. 2010;47(2):175–82.PubMedCrossRef

Title: Molecular Mechanisms of PINK1-Related Neurodegeneration
Authors: Joe H. Pogson
Rachael M. Ivatt
Alexander J. Whitworth
Publication date: 01-06-2011
Publisher: Current Science Inc.
Published in: Current Neurology and Neuroscience Reports / Issue 3/2011
Print ISSN: 1528-4042
Electronic ISSN: 1534-6293
DOI: https://doi.org/10.1007/s11910-011-0187-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Molecular Mechanisms of PINK1-Related Neurodegeneration

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2011

Current State of Our Knowledge on Brain Tumor Epidemiology

Alzheimer’s Genetics in the GWAS Era: A Continuing Story of ‘Replications and Refutations’

Recent Advances in the Genetics of Hereditary Axonal Sensory-Motor Neuropathies Type 2

NMDA Receptor Antibody Encephalitis

Modeling Neurodegeneration in Zebrafish

Patterns of Progression in Malignant Glioma Following Anti-VEGF Therapy: Perceptions and Evidence