title: Iron-Starvation-Induced Mitophagy Mediates Lifespan Extension upon Mitochondrial Stress in C. elegans.
abstract: Frataxin is a nuclear-encoded mitochondrial protein involved in the biogenesis of Fe-S-cluster-containing proteins and consequently in the functionality of the mitochondrial respiratory chain. Similar to other proteins that regulate mitochondrial respiration, severe frataxin deficiency leads to pathology in humans--Friedreich's ataxia, a life-threatening neurodegenerative disorder--and to developmental arrest in the nematode C. elegans. Interestingly, partial frataxin depletion extends C. elegans lifespan, and a similar anti-aging effect is prompted by reduced expression of other mitochondrial regulatory proteins from yeast to mammals. The beneficial adaptive responses to mild mitochondrial stress are still largely unknown and, if characterized, may suggest novel potential targets for the treatment of human mitochondria-associated, age-related disorders. Here we identify mitochondrial autophagy as an evolutionarily conserved response to frataxin silencing, and show for the first time that, similar to mammals, mitophagy is activated in C. elegans in response to mitochondrial stress in a pdr-1/Parkin-, pink-1/Pink-, and dct-1/Bnip3-dependent manner. The induction of mitophagy is part of a hypoxia-like, iron starvation response triggered upon frataxin depletion and causally involved in animal lifespan extension. We also identify non-overlapping hif-1 upstream (HIF-1-prolyl-hydroxylase) and downstream (globins) regulatory genes mediating lifespan extension upon frataxin and iron depletion. Our findings indicate that mitophagy induction is part of an adaptive iron starvation response induced as a protective mechanism against mitochondrial stress, thus suggesting novel potential therapeutic strategies for the treatment of mitochondrial-associated, age-related disorders.
authors.affiliation: IUF-Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany; Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Schiavi
authors.affiliation: Institute for Clinical Chemistry and Laboratory Diagnostic, Medical Faculty of the Heinrich Heine University, 40225 Düsseldorf, Germany; IUF-Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Maglioni
authors.affiliation: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas, Heraklion 70013, Crete, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Palikaras
authors.affiliation: Institute for Clinical Chemistry and Laboratory Diagnostic, Medical Faculty of the Heinrich Heine University, 40225 Düsseldorf, Germany; IUF-Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany.
authors.forename: Anjumara
authors.initials: A
authors.lastname: Shaik
authors.affiliation: IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Flavie
authors.initials: F
authors.lastname: Strappazzon
authors.affiliation: IUF-Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Brinkmann
authors.affiliation: IUF-Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Torgovnick
authors.affiliation: Biology Department, Ghent University, 9000 Ghent, Belgium.
authors.forename: Natascha
authors.initials: N
authors.lastname: Castelein
authors.affiliation: Biology Department, Ghent University, 9000 Ghent, Belgium.
authors.forename: Sasha
authors.initials: S
authors.lastname: De Henau
authors.affiliation: Biology Department, Ghent University, 9000 Ghent, Belgium.
authors.forename: Bart P
authors.initials: BP
authors.lastname: Braeckman
authors.affiliation: IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy; Unit of Cell Stress and Survival, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cecconi
authors.affiliation: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas, Heraklion 70013, Crete, Greece; Department of Basic Sciences, Faculty of Medicine, University of Crete, Heraklion 71110, Crete, Greece.
authors.forename: Nektarios
authors.initials: N
authors.lastname: Tavernarakis
authors.affiliation: Institute for Clinical Chemistry and Laboratory Diagnostic, Medical Faculty of the Heinrich Heine University, 40225 Düsseldorf, Germany; IUF-Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany; Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy. Electronic address: natascia.ventura@uni-duesseldorf.de.
authors.forename: Natascia
authors.initials: N
authors.lastname: Ventura
mesh_terms: D000693:Anaerobiosis; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D005215:Fasting; D000090463:Iron Deficiencies; D033862:Iron-Binding Proteins; D008136:Longevity / Q000187:drug effects; D063306:Mitophagy / Q000187:drug effects*; D000096923:Frataxin
chemical_list: D029742:Caenorhabditis elegans Proteins; D033862:Iron-Binding Proteins; D000096923:Frataxin