Molecular Gene Therapy: Overexpression of the Alternative NADH Dehydrogenase NDI1 Restores Overall Physiology in a Fungal Model of Respiratory Complex I Deficiency

• Published in: Journal of molecular biology 2010-05, Vol.399 (1), p.31-40
• Main Authors: Maas, Marc F.P.M., Sellem, Carole H., Krause, Frank, Dencher, Norbert A., Sainsard-Chanet, Annie
• Format: Article
• Language: English
• Subjects: alternative respiratory pathway; Electron Transport - physiology; Electron Transport Complex I - genetics; Electron Transport Complex I - metabolism; Genetic Therapy; life span; Mitochondria - enzymology; Mitochondria - metabolism; NADH Dehydrogenase - genetics; NADH Dehydrogenase - metabolism; NADH:ubiquinone oxidoreductase; Podospora - enzymology; Podospora - genetics; Podospora anserina; respiratory supercomplexes
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2010.04.015

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.