Counteracting ferroptosis through frataxin silencing may be a novel therapeutic approach in the treatment of neurodegenerative conditions such as Friedreich ataxia (FA), as it seems to protect against hypoxia-, age-, and proteotoxicity-induced neuromuscular deficits in Caenorhabditis elegans, according to an article published in iScience.
To examine if genetic and chemical interventions acting via mild iron can prevent neuromuscular damage as efficiently as hypoxia preconditioning, the researchers limited iron availability in C. elegans using frataxin silencing or the iron chelator bipyridine.
According to the results, sublethal iron deficiency could protect against hypoxia-induced neuromuscular damage in the nematode. Prolongevity frataxin deficits could also prevent hypoxia- and age-induced proteotoxicity.
The depletion of frataxin was found to extend the lifespan of C. elegans, mainly through glutathione/glutathione peroxidase-dependent and -independent mechanisms. However, supplementation with dihomo-gamma-linolenic acid partially suppressed the lifespan extension achieved by the activity of iron competing agents.
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Moreover, frataxin deficiency affected the neuroimmune, detoxification, metabolic, and redox regulatory processes across the lifespan of C. elegans.
“Ferroptosis is a form of glutathione-regulated non-apoptotic cell death mediated by iron-induced lipid peroxidation and our work indicates frataxin depletion impact on different key ferroptosis players, “ Schiavi and colleagues wrote. “Namely, frataxin silencing RNA interference in C. elegans increases the pool of reduced glutathione and decreases iron reactive oxygen species and lipid content, all factors which can clearly concur to limit ferroptosis cell death. Our data strongly point toward regulation of lipid metabolic processes modulated by frataxin to suppress ferroptosis.”
Both the excess and depletion of iron can cause pathological transformations of human cells, as well as lead to developmental difficulties in C. elegans. However, sublethal iron depletion is likely associated with various beneficial effects.
Reference
Schiavi A, Salveridou E, Brinkmann V, et al. Mitochondria hormesis delays aging and associated diseases in Caenorhabditis elegans impacting on key ferroptosis players. iScience. Published March 21, 2023. doi:10.1016/j.isci.2023.106448
