title: Expression of yeast NDI1 rescues a Drosophila complex I assembly defect.
abstract: Defects in mitochondrial electron transport chain (ETC) function have been implicated in a number of neurodegenerative disorders, cancer, and aging. Mitochondrial complex I (NADH dehydrogenase) is the largest and most complicated enzyme of the ETC with 45 subunits originating from two separate genomes. The biogenesis of complex I is an intricate process that requires multiple steps, subassemblies, and assembly factors. Here, we report the generation and characterization of a Drosophila model of complex I assembly factor deficiency. We show that CG7598 (dCIA30), the Drosophila homolog of human complex I assembly factor Ndufaf1, is necessary for proper complex I assembly. Reduced expression of dCIA30 results in the loss of the complex I holoenzyme band in blue-native polyacrylamide gel electrophoresis and loss of NADH:ubiquinone oxidoreductase activity in isolated mitochondria. The complex I assembly defect, caused by mutation or RNAi of dCIA30, has repercussions both during development and adulthood in Drosophila, including developmental arrest at the pupal stage and reduced stress resistance during adulthood. Expression of the single-subunit yeast alternative NADH dehydrogenase, Ndi1, can partially or wholly rescue phenotypes associated with the complex I assembly defect. Our work shows that CG7598/dCIA30 is a functional homolog of Ndufaf1 and adds to the accumulating evidence that transgenic NDI1 expression is a viable therapy for disorders arising from complex I deficiency.
authors.affiliation: Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Jaehyoung
authors.initials: J
authors.lastname: Cho
authors.forename: Jae H
authors.initials: JH
authors.lastname: Hur
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Graniel
authors.forename: Seymour
authors.initials: S
authors.lastname: Benzer
authors.forename: David W
authors.initials: DW
authors.lastname: Walker
mesh_terms: D000818:Animals; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000172:deficiency / Q000235:genetics*; D015870:Gene Expression; D020035:Holoenzymes / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D028361:Mitochondrial Diseases / Q000235:genetics / Q000628:therapy; D009245:NADH Dehydrogenase / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D034622:RNA Interference; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: D020035:Holoenzymes; C493237:Ndi1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C506342:NDUFAF1 protein, human