Defects in the expression of the mitochondrial protein frataxin cause Friedreichs Ataxia (FA), the most frequently inherited ataxia associated with neurodegeneration and reduced life expectancy in humans. We recently established a C. elegans model of FA. Paradoxically, reducing frataxin (
frh-1) levels in worms increased lifespan. Similar to other long-lived Mitochondrial mutants (both RNAi- and genetically-defined), developmental rate and fertility were both decreased in
frh-1 mutants. We recently proposed that multiple stress-response pathways are induced in the Mit mutants to counteract their mitochondrial deficits and that ultimately these pathways act to specify all aspects of the Mit phenotype. Once mitochondrial dysfunction becomes too severe, however, these pathways no longer support animal viability and presumably result in deleterious consequences. Degeneration of frataxin-deficient cells is mostly attributable to inefficient mitochondrial energy metabolism leading to low ATP and/or high ROS production. Recently, alterations in energy metabolism were shown to cause
p53-dependent cell cycle arrest in both Drosophila melanogaster and mammalian cells. We now find that the life extension of the
frh-1 Mit mutant (as well as three other Mit mutants,
atp-3,
isp-1,
cco-1), is under the regulation of
cep-1, the C. elegans homologue of
p53. In mammalian cells,
p53 induces different cellular responses depending on the type and level of stress controlling its activation. Interestingly, in a similar manner, we find that
cep-1 differentially controls Mit mutant lifespan depending on the level of mitochondrial dysfunction. We are using our model to gain insight into the pathogenesis of FA and of other mitochondrial-associated diseases.