title: Can a single subunit yeast NADH dehydrogenase (Ndi1) remedy diseases caused by respiratory complex I defects?
abstract: The proton-translocating NADH-quinone oxidoreductase (complex I) is one of five enzyme complexes in the oxidative phosphorylation system in mammalian mitochondria. Complex I is composed of 46 different subunits, 7 of which are encoded by mitochondrial DNA. Defects of complex I are involved in many human mitochondrial diseases; therefore, the authors proposed to use the NDI1 gene encoding a single subunit NADH dehydrogenase of Saccharomyces cerevisiae for repair of respiratory activity. The yeast NDI1 gene was successfully introduced into 10 mammalian cell lines (two of which were complex I-deficient mutants). The expressed Ndi1 protein was correctly targeted to the matrix side of the inner mitochondrial membranes, was fully functional, and restored the NADH oxidase activity to the complex I-deficient cells. The NDI1-transduced cells were more resistant to complex I inhibitors and diminished production of reactive oxygen species. It was further shown that the Ndi1 protein can be functionally expressed in tissues such as skeletal muscles and brain of rodents. The Ndi1 expression scarcely induced an inflammatory response as assessed by hematoxylin and eosin (H&E) staining. The Ndi1 protein expressed in the substantia nigra (SN) elicited protective effects against neurodegeneration caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. The Ndi1 protein has a great potential as a molecular remedy for complex I deficiencies.
authors.affiliation: Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Reseach Institute, La Jolla, California 92037, USA. yagi@scripps.edu
authors.forename: Takao
authors.initials: T
authors.lastname: Yagi
authors.forename: Byoung Boo
authors.initials: BB
authors.lastname: Seo
authors.forename: Eiko
authors.initials: E
authors.lastname: Nakamaru-Ogiso
authors.forename: Mathieu
authors.initials: M
authors.lastname: Marella
authors.forename: Jennifer
authors.initials: J
authors.lastname: Barber-Singh
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Yamashita
authors.forename: Mou-Chieh
authors.initials: MC
authors.lastname: Kao
authors.forename: Akemi
authors.initials: A
authors.lastname: Matsuno-Yagi
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D017237:Mitochondrial Encephalomyopathies; D018482:Muscle, Skeletal / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000494:pharmacology
chemical_list: C493237:Ndi1 protein, S cerevisiae; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I