Caenorhabditis elegans model for Friedreichs ataxia: investigate the role of autophagy in longevity and neurodegeneration

Severemitochondriadeficiencyleadstoanumberofdevastatingdegenerativedisorders,yet,mildmitochondrialdysfunctionindifferentspecies,includingthenematodeCaenorhabditiselegans(C.elegans),canhavepro-longevity effects. We previously proposed that, following mild mitochondrial stress, protective stress responses pathways are activated in a hormetic-like fashion, andultimatelyaccountforextendedanimalslifespan. Frataxin(frh-1inC.elegans)isamitochondrialproteinmainlyinvolvediniron-sulfurclustersbiogenesis 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. Wefoundthatp53/cep-1hasalsoamajorroleinthecontrolofautophagy afterRNAi-mediatedfrh-1suppression. Specifically,wefoundthatBeclinand p53genesarerequiredtoinduceautophagyandconcurrentlyreducelipidstorages 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, protectiveresponseactivatedtocopewithmitochondriadysfunction,andindicatenewpotentialtherapeuticstrategiesforthetreatmentofFriedreichsataxia and possibly other human mitochondria-associated disorder.