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Morais, V.* ; Verstreken, P.* ; Roethig, A. ; Smet, J.* ; Snellinx, A.* ; Vanbrabant, M.* ; Haddad, D.* ; Frezza, C.* ; Mandemakers, W.* ; Vogt Weisenhorn, D.M. ; van Coster, R.* ; Wurst, W. ; Scorrano, L.* ; de Strooper, B.*

Parkinson's disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function.

EMBO Mol. Med. 1, 99-111 (2009)
Publ. Version/Full Text Volltext DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Mutations of the mitochondrial PTEN (phosphatase and tensin homologue)-induced kinase1 (PINK1) are important causes of recessive Parkinson disease (PD). Studies on loss of function and overexpression implicate PINK1 in apoptosis, abnormal mitochondrial morphology, impaired dopamine release and motor deficits. However, the fundamental mechanism underlying these various phenotypes remains to be clarified. Using fruit fly and mouse models we show that PINK1 deficiency or clinical mutations impact on the function of Complex I of the mitochondrial respiratory chain, resulting in mitochondrial depolarization and increased sensitivity to apoptotic stress in mammalian cells and tissues. In Drosophila neurons, PINK1 deficiency affects synaptic function, as the reserve pool of synaptic vesicles is not mobilized during rapid stimulation. The fundamental importance of PINK1 for energy maintenance under increased demand is further corroborated as this deficit can be rescued by adding ATP to the synapse. The clinical relevance of our observations is demonstrated by the fact that human wild type PINK1, but not PINK1 containing clinical mutations, can rescue Complex 1 deficiency. Our work suggests that Complex I deficiency underlies, at least partially, the pathogenesis of this hereditary form of PD. As Complex I dysfunction is also implicated in sporadic PD, a convergence of genetic and environmental causes of PD on a similar mitochondrial molecular mechanism appears to emerge.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Complex I; mitochondrial dysfunction; Parkinson's disease; reserve pool deficit; PERMEABILITY TRANSITION PORE; MITOCHONDRIAL DYSFUNCTION; OXIDATIVE STRESS; ALPHA-SYNUCLEIN; RECESSIVE PARKINSONISM; INCREASED SENSITIVITY; CELL-DEATH; DROSOPHILA; APOPTOSIS; PROTEIN
ISSN (print) / ISBN 1757-4676
e-ISSN 1757-4684
Journal EMBO Molecular Medicine
Quellenangaben Volume: 1, Issue: 2, Pages: 99-111 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Chichester
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)