Molecular gene therapy: overexpression of the alternative NADH dehydrogenase NDI1 restores overall physiology in a fungal model of respiratory complex I deficiency.
Defects in oxidative phosphorylation lie at the heart of a wide variety of degenerative disorders, cancer, and aging. Here, we show, using the fungal model Podospora anserina, that the overexpression of the native mitochondrial matrix-faced type II NADH dehydrogenase NDI1, paralogue of the human apoptosis inducing factor AIF1, can fully restore all physiological consequences of respiratory complex I deficiency. We disrupted the 19.3-kDa subunit of the complex I catalytic core, orthologue of the human PSST subunit, leading to a complete absence of the complex without affecting the assembly and/or stability of the rest of the respiratory chain. This disruption caused a several-fold life span extension at the expense of both male and female fertility. The effect was generally similar but markedly milder than that caused by defects in the complex III/IV-dependent pathway and not associated with a clear reduction in the steady-state level of mitochondrial reactive oxygen species. Whereas the native expression of NDI1 was sufficient to overcome lethality, only the artificial, constitutive overexpression of NDI1 could fully remedy this deficiency: The latter strikingly restored both life span and fertility to levels indistinguishable from wild type, thus demonstrating its unique potential in molecular gene therapy.
Maas
Marc F P M
MF
Centre de Génétique Moléculaire, Centre National de la Recherche Scientifique, 91198 Gif sur Yvette Cedex, France. m.f.p.m.maas@rug.nl
Sellem
Carole H
CH
Krause
Frank
F
Dencher
Norbert A
NA
Sainsard-Chanet
Annie
A
D004579:Electron Transport / Q000502:physiology; D042967:Electron Transport Complex I / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D048468:Podospora / Q000201:enzymology* / Q000235:genetics
D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I