title: PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling.
abstract: Under resting conditions, Pink1 knockout cells and cells derived from patients with PINK1 mutations display a loss of mitochondrial complex I reductive activity, causing a decrease in the mitochondrial membrane potential. Analyzing the phosphoproteome of complex I in liver and brain from Pink1(-/-) mice, we found specific loss of phosphorylation of serine-250 in complex I subunit NdufA10. Phosphorylation of serine-250 was needed for ubiquinone reduction by complex I. Phosphomimetic NdufA10 reversed Pink1 deficits in mouse knockout cells and rescued mitochondrial depolarization and synaptic transmission defects in pink(B9)-null mutant Drosophila. Complex I deficits and adenosine triphosphate synthesis were also rescued in cells derived from PINK1 patients. Thus, this evolutionary conserved pathway may contribute to the pathogenic cascade that eventually leads to Parkinson's disease in patients with PINK1 mutations.
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium.
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: Morais
authors.forename: Dominik
authors.initials: D
authors.lastname: Haddad
authors.forename: Katleen
authors.initials: K
authors.lastname: Craessaerts
authors.forename: Pieter-Jan
authors.initials: PJ
authors.lastname: De Bock
authors.forename: Jef
authors.initials: J
authors.lastname: Swerts
authors.forename: Sven
authors.initials: S
authors.lastname: Vilain
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Aerts
authors.forename: Lut
authors.initials: L
authors.lastname: Overbergh
authors.forename: Anne
authors.initials: A
authors.lastname: Grünewald
authors.forename: Philip
authors.initials: P
authors.lastname: Seibler
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.forename: Kris
authors.initials: K
authors.lastname: Gevaert
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000201:enzymology; D029721:Drosophila Proteins / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000201:enzymology; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D009245:NADH Dehydrogenase / Q000378:metabolism*; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics*; D010766:Phosphorylation / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics*; D020543:Proteome; D012694:Serine / Q000737:chemistry / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D029721:Drosophila Proteins; D042967:Electron Transport Complex I; D009245:NADH Dehydrogenase; D011494:Protein Kinases; D020543:Proteome; D012694:Serine; D000099202:PTEN-Induced Putative Kinase; C000602554:ND-42 protein, Drosophila; C588033:NdufA10 protein, mouse