Caenorhabditis elegans model for Friedreich's ataxia: investigate the role of autophagy in longevity and neurodegeneration

Severe mitochondria deficiency leads to a number of devastating degenerative disorders, yet, mild mitochondrial dysfunction in different species, including the nematode Caenorhabditis elegans (C. elegans), can have pro-longevity effects. We previously proposed that, following mild mitochondrial stress, protective stress responses pathways are activated in a hormetic-like fashion, and ultimately account for extended animals lifespan. Frataxin (frh-1 in C. elegans) is a mitochondrial protein mainly involved in iron-sulfur clusters biogenesis and iron homeostasis. Complete absence of frataxin is lethal in different species including C. elegans; its severe deficiency in human leads to Friedreichs ataxia, the most common inherited recessive ataxia; while its expression is increased in different human tumors. We recently showed that cep-1, the C. elegans homologue of the p53 family members is required for stress response and lifespan extension upon disruption of different electron transport chain (ETC) proteins. Nevertheless, how partial frataxin depletion elicits its prolongevity response it is still largely unknown. The aim of this project was to use C. elegans as a genetic tool to unravel whether and how autophagy can be activated as compensatory mechanisms in response to mitochondrial dysfunction. We found that p53/cep-1 has also a major role in the control of autophagy after RNAi-mediated frh-1 suppression. Specifically, we found that Beclin and p53 genes are required to induce autophagy and concurrently reduce lipid storages and extend animal lifespan in response to frataxin suppression. Reciprocally, frataxin expression modulates autophagy in the absence of p53. Human Friedreich ataxia-derived lymphoblasts also display increased autophagy, indicating an evolutionarily conserved response to reduced frataxin expression. We also observed that frh-1 RNAi requires the hypoxia-inducible factor HIF1 to extend lifespan and induce autophagy, and modulates the expression of globin genes, which encode for oxygen-binding iron-containing proteins. Interestingly, we show for the first time that the lifespan extension elicited by frh-1 RNAi is triggered by the hypoxia mimetic effect of iron deprivation requires mitophagy-regulatory genes. Our results suggest that induction of mitochondria autophagy through a hypoxia-like environment is a pro-longevity, protective response activated to cope with mitochondria dysfunction, and indicate new potential therapeutic strategies for the treatment of Friedreichs ataxia and possibly other human mitochondria-associated disorder.