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

Alfonso Schiavi; Eva Salveridou; Vanessa Brinkmann; Anjumara Shaik; Ralph Menzel; Sumana Kalyanasundaram; Ståle Nygård; Hilde Nilsen; Natascia Ventura

doi:10.1016/j.isci.2023.106448

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

iScience. 2023 Mar 21;26(4):106448. doi: 10.1016/j.isci.2023.106448. eCollection 2023 Apr 21.

Authors

Alfonso Schiavi¹, Eva Salveridou¹, Vanessa Brinkmann¹, Anjumara Shaik¹, Ralph Menzel², Sumana Kalyanasundaram³, Ståle Nygård⁴, Hilde Nilsen³, Natascia Ventura^{1

5}

Affiliations

¹ Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany.
² Humboldt-Universität zu Berlin, Berlin, Germany.
³ Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.
⁴ Bioinformatics Core Facility, Institute for Medical Informatics, Oslo University Hospital, Oslo, Norway.
⁵ Institute of Clinical Chemistry and Laboratory Diagnostic, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.

Abstract

Excessive iron accumulation or deficiency leads to a variety of pathologies in humans and developmental arrest in the nematode Caenorhabditis elegans. Instead, sub-lethal iron depletion extends C. elegans 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 C. elegans 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 gpx-independent redox systems. We thus point to ferroptosis inhibition as a novel potential strategy to promote healthy aging.

Keywords: Cell biology; Cellular neuroscience; Cellular physiology.