Mutations in two zinc-cluster proteins activate alternative respiratory and gluconeogenic pathways and restore senescence in long-lived respiratory mutants of Podospora anserina.

In Podospora anserina, inactivation of the respiratory chain results in a spectacular life-span extension. This inactivation is accompanied by the induction of the alternative oxidase. Although the functional value of this response is evident, the mechanism behind it is far from understood. By screening suppressors able to reduce the life-span extension of cytochrome-deficient mutants, we identified mutations in two zinc-cluster proteins, RSE2 and RSE3, which are conserved in other ascomycetes. These mutations led to the overexpression of the genes encoding the alternative oxidase and the gluconeogenic enzymes, fructose-1, 6 biphosphatase, and pyruvate carboxykinase. Both RSE2 and RSE3 are required for the expression of these genes. We also show that, even in the absence of a respiratory deficiency, the wild-type RSE2 and RSE3 transcription factors are involved in life-span control and their inactivation retards aging. These data are discussed with respect to aging, the regulation of the alternative oxidase, and carbon metabolism.