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 apo...

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Bibliographic Details
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
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Summary: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.
ISSN:0022-2836
1089-8638
DOI:10.1016/j.jmb.2010.04.015