Can a single subunit yeast NADH dehydrogenase (Ndi1) remedy diseases caused by respiratory complex I defects?
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.
Yagi
Takao
T
Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Reseach Institute, La Jolla, California 92037, USA. yagi@scripps.edu
Seo
Byoung Boo
BB
Nakamaru-Ogiso
Eiko
E
Marella
Mathieu
M
Barber-Singh
Jennifer
J
Yamashita
Tetsuo
T
Kao
Mou-Chieh
MC
Matsuno-Yagi
Akemi
A
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
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