title: A Drosophila model of mitochondrial disease caused by a complex I mutation that uncouples proton pumping from electron transfer.
abstract: Mutations affecting mitochondrial complex I, a multi-subunit assembly that couples electron transfer to proton pumping, are the most frequent cause of heritable mitochondrial diseases. However, the mechanisms by which complex I dysfunction results in disease remain unclear. Here, we describe a Drosophila model of complex I deficiency caused by a homoplasmic mutation in the mitochondrial-DNA-encoded NADH dehydrogenase subunit 2 (ND2) gene. We show that ND2 mutants exhibit phenotypes that resemble symptoms of mitochondrial disease, including shortened lifespan, progressive neurodegeneration, diminished neural mitochondrial membrane potential and lower levels of neural ATP. Our biochemical studies of ND2 mutants reveal that complex I is unable to efficiently couple electron transfer to proton pumping. Thus, our study provides evidence that the ND2 subunit participates directly in the proton pumping mechanism of complex I. Together, our findings support the model that diminished respiratory chain activity, and consequent energy deficiency, are responsible for the pathogenesis of complex-I-associated neurodegeneration.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jonathon L
authors.initials: JL
authors.lastname: Burman
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Itsara
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: Ernst-Bernhard
authors.initials: EB
authors.lastname: Kayser
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: Wichit
authors.initials: W
authors.lastname: Suthammarak
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Kaeberlein
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Sedensky
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, WA 98101, USA. pgm4@uw.edu pallanck@uw.edu.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Morgan
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. pgm4@uw.edu pallanck@uw.edu.
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Pallanck
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004330:Drosophila; D004579:Electron Transport; D042967:Electron Transport Complex I / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism; D009154:Mutation; D010085:Oxidative Phosphorylation; D017494:Proton Pumps / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017494:Proton Pumps; D017382:Reactive Oxygen Species; D042967:Electron Transport Complex I
keywords: Drosophila; Leigh syndrome; Mitochondria; Mitochondrial disease; Neurodegeneration; Respiratory chain
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