title: The yeast complex I equivalent NADH dehydrogenase rescues pink1 mutants.
abstract: Pink1 is a mitochondrial kinase involved in Parkinson's disease, and loss of Pink1 function affects mitochondrial morphology via a pathway involving Parkin and components of the mitochondrial remodeling machinery. Pink1 loss also affects the enzymatic activity of isolated Complex I of the electron transport chain (ETC); however, the primary defect in pink1 mutants is unclear. We tested the hypothesis that ETC deficiency is upstream of other pink1-associated phenotypes. We expressed Saccaromyces cerevisiae Ndi1p, an enzyme that bypasses ETC Complex I, or sea squirt Ciona intestinalis AOX, an enzyme that bypasses ETC Complex III and IV, in pink1 mutant Drosophila and find that expression of Ndi1p, but not of AOX, rescues pink1-associated defects. Likewise, loss of function of subunits that encode for Complex I-associated proteins displays many of the pink1-associated phenotypes, and these defects are rescued by Ndi1p expression. Conversely, expression of Ndi1p fails to rescue any of the parkin mutant phenotypes. Additionally, unlike pink1 mutants, fly parkin mutants do not show reduced enzymatic activity of Complex I, indicating that Ndi1p acts downstream or parallel to Pink1, but upstream or independent of Parkin. Furthermore, while increasing mitochondrial fission or decreasing mitochondrial fusion rescues mitochondrial morphological defects in pink1 mutants, these manipulations fail to significantly rescue the reduced enzymatic activity of Complex I, indicating that functional defects observed at the level of Complex I enzymatic activity in pink1 mutant mitochondria do not arise from morphological defects. Our data indicate a central role for Complex I dysfunction in pink1-associated defects, and our genetic analyses with heterologous ETC enzymes suggest that Ndi1p-dependent NADH dehydrogenase activity largely acts downstream of, or in parallel to, Pink1 but upstream of Parkin and mitochondrial remodeling.
authors.affiliation: VIB Center for Biology of Disease, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Sven
authors.initials: S
authors.lastname: Vilain
authors.forename: Giovanni
authors.initials: G
authors.lastname: Esposito
authors.forename: Dominik
authors.initials: D
authors.lastname: Haddad
authors.forename: Onno
authors.initials: O
authors.lastname: Schaap
authors.forename: Mariya P
authors.initials: MP
authors.lastname: Dobreva
authors.forename: Melissa
authors.initials: M
authors.lastname: Vos
authors.forename: Stefanie
authors.initials: S
authors.lastname: Van Meensel
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: Morais
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics / Q000378:metabolism; D002938:Ciona intestinalis / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism*; D014450:Electron Transport Complex III / Q000235:genetics / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009154:Mutation; D010088:Oxidoreductases / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics; D010940:Plant Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000099188:Alternative Oxidase; D000099202:PTEN-Induced Putative Kinase
chemical_list: D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; D003576:Electron Transport Complex IV; D019204:GTP-Binding Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D010088:Oxidoreductases; D010940:Plant Proteins; D017346:Protein Serine-Threonine Kinases; D029701:Saccharomyces cerevisiae Proteins; D044767:Ubiquitin-Protein Ligases; D000099188:Alternative Oxidase; C493237:Ndi1 protein, S cerevisiae; C527116:OPA1 protein, Drosophila; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase; C504426:DRP1 protein, Drosophila; C487430:park protein, Drosophila