title: Alternative oxidase rescues mitochondria-mediated dopaminergic cell loss in Drosophila.
abstract: Mitochondrial dysfunction is commonly observed in degenerative disorders, including Alzheimer's and Parkinson's disease that are characterized by the progressive and selective loss of neuronal subpopulations. It is currently unclear, however, whether mitochondrial dysfunction is primary or secondary to other pathogenic processes that eventually lead to age-related neurodegeneration. Here we establish an in vivo Drosophila model of mitochondrial dysfunction by downregulating the catalytic subunit of mitochondrial DNA (mtDNA) polymerase in cholinergic, serotonergic and dopaminergic neurons. The resulting flies are characterized by lowered respiratory chain activity, premature aging, age-related motor deficits as well as adult onset, progressive and cell-type-specific, dopaminergic neurodegeneration. Using this model, we find that associated lethality can be partially rescued by targeting PINK1/parkin signaling or Drp1, both of which have been implicated in mitochondrial dynamics and Parkinson's disease. Bypassing mitochondrial complex III/IV deficiencies with Alternative oxidase (AOX), however, fully restores ATP levels and prevents dopaminergic neurodegeneration. In contrast, ATP levels and neurodegeneration are not rescued when mitochondrial complex I deficiencies are bypassed with NADH-Q oxidoreductase. Our results demonstrate that mtDNA-mediated mitochondrial dysfunction can cause age-related and cell-type-specific neurodegeneration which AOX is able to alleviate and indicate that AOX or its surrogates may prove useful as a therapeutic tool for limiting respiratory chain deficiencies caused by mtDNA decline in healthy aging and neurodegenerative disease.
authors.affiliation: MRC Centre for Neurodegeneration Research, King’s College London, Institute of Psychiatry, Department of Neuroscience, King’s College London, London, UK.
authors.forename: Dickon M
authors.initials: DM
authors.lastname: Humphrey
authors.forename: Richard B
authors.initials: RB
authors.lastname: Parsons
authors.forename: Zoe N
authors.initials: ZN
authors.lastname: Ludlow
authors.forename: Thomas
authors.initials: T
authors.lastname: Riemensperger
authors.forename: Giovanni
authors.initials: G
authors.lastname: Esposito
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
authors.forename: Howard T
authors.initials: HT
authors.lastname: Jacobs
authors.forename: Serge
authors.initials: S
authors.lastname: Birman
authors.forename: Frank
authors.initials: F
authors.lastname: Hirth
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D004579:Electron Transport / Q000235:genetics; D042967:Electron Transport Complex I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D010940:Plant Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D000099188:Alternative Oxidase
chemical_list: D000255:Adenosine Triphosphate; D003598:Cytoskeletal Proteins; D004272:DNA, Mitochondrial; D004259:DNA-Directed DNA Polymerase; D029721:Drosophila Proteins; D042967:Electron Transport Complex I; D019204:GTP-Binding Proteins; D024101:Mitochondrial Proteins; D009247:NADH, NADPH Oxidoreductases; D010088:Oxidoreductases; D010940:Plant Proteins; D044767:Ubiquitin-Protein Ligases; D000099188:Alternative Oxidase; C504426:DRP1 protein, Drosophila; C487430:park protein, Drosophila