Partial frataxin suppression in Caenorhabditis elegans reduces tumor formation by dampening the RAS/MAPk signaling

Frataxin is a nuclear encoded mitochondrial protein entailed in the assembly and repair of iron-sulphur (Fe-S) clusters and in cellular iron homeostasis (Bencze et al., 2006). Several components of mitochondrial electron transport chain (ETC) contain Fe-S clusters, and hence frataxin is vital for mitochondrial functionality. Severe frataxin deficiency leads, as it would be expected by severe mitochondrial dysfunction, to detrimental effects including arrested development and shortened lifespan in Caenorhabditis elegans and a life-threatening neurodegenerative disease in humans, Friedriech’s Ataxia (FRDA). On the other hand, intriguingly, convincing studies from our lab reported that partial frataxin inactivation via RNA interference (RNAi) substantially extends the lifespan of C. elegans within a defined window of mitochondrial ETC impairment (Ventura et al., 2005, Rea et al., 2007, Schiavi et al., 2013). Further studies from our lab have shown that the opposite biological consequences in response to the different degree of mitochondrial alteration, are part of a hormetic stress response (a phenomenon by which beneficial processes are triggered upon mild doses of a stress which is otherwise toxic at higher doses). Namely, mild mitochondrial stress results in the activation of cellular compensatory processes, such as cep-1/p53-regulated autophagy, DNA repair pathways and mitophagy which concur to provide protection against moderate mitochondrial stress, eventually increasing animal resistance to stress and healthy lifespan (Ventura et al., 2009, Schiavi et al., 2013, Torgovnick et al., 2010, Schiavi et al., 2015). Aging and cancer are intrinsically coupled. It is widely established that cellular damage accumulation is the major perpetrator that drives both aging and cancer. This notion highlights the fact that those mechanisms which are prompted to combat aging, are in many cases the same that provide an anti-cancer effect (Anisimov, 2001, Serrano and Blasco, 2007). Thus, the aim of my Ph.D. project was to investigate if the anti-aging effect elicited by partial frataxin inactivation might also confer tumor suppressor activity using C. elegans as a model to study cancer. We found that moderate levels of frataxin inactivation via RNAi attenuates the deleterious effects, conceivably in a tissue-specific manner, and prevents premature organismal death caused by tumorigenic mutations in C. elegans. These observations suggest that making mitochondria work at the optimal level through partial frataxin depletion concurrently confers anti-aging and tumor suppressor activity.