title: Parkinson's disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function.
abstract: 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.
authors.affiliation: Center for Human Genetics, K.U. Leuven, Leuven, Belgium.
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: Morais
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
authors.forename: Anne
authors.initials: A
authors.lastname: Roethig
authors.forename: Joél
authors.initials: J
authors.lastname: Smet
authors.forename: An
authors.initials: A
authors.lastname: Snellinx
authors.forename: Mieke
authors.initials: M
authors.lastname: Vanbrabant
authors.forename: Dominik
authors.initials: D
authors.lastname: Haddad
authors.forename: Christian
authors.initials: C
authors.lastname: Frezza
authors.forename: Wim
authors.initials: W
authors.lastname: Mandemakers
authors.forename: Daniela
authors.initials: D
authors.lastname: Vogt-Weisenhorn
authors.forename: Rudy
authors.initials: R
authors.lastname: Van Coster
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Luca
authors.initials: L
authors.lastname: Scorrano
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
mesh_terms: D000818:Animals; D017209:Apoptosis; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics*; D004331:Drosophila melanogaster / Q000201:enzymology; D004579:Electron Transport; D042967:Electron Transport Complex I / Q000378:metabolism*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics*; D013569:Synapses / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000502:physiology; D000099202:PTEN-Induced Putative Kinase
chemical_list: D029721:Drosophila Proteins; D042967:Electron Transport Complex I; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D000099202:PTEN-Induced Putative Kinase; C534484:PINK1 protein, Drosophila