Mitochondria hormesis delays aging and associated diseases in impacting on key ferroptosis players.

Excessive iron accumulation or deficiency leads to a variety of pathologies in humans and developmental arrest in the nematode . Instead, sub-lethal iron depletion extends lifespan. Hypoxia preconditioning protects against severe hypoxia-induced neuromuscular damage across species but it has low feasible application. In this study, we assessed the potential beneficial effects of genetic and chemical interventions acting via mild iron instead of oxygen depletion. We show that limiting iron availability in through frataxin silencing or the iron chelator bipyridine, similar to hypoxia preconditioning, protects against hypoxia-, age-, and proteotoxicity-induced neuromuscular deficits. Mechanistically, our data suggest that the beneficial effects elicited by frataxin silencing are in part mediated by counteracting ferroptosis, a form of non-apoptotic cell death mediated by iron-induced lipid peroxidation. This is achieved by impacting on different key ferroptosis players and likely via -independent redox systems. We thus point to ferroptosis inhibition as a novel potential strategy to promote healthy aging.