TAp73 depletion accelerates aging through metabolic dysregulation
- Alessandro Rufini1,
- Maria Victoria Niklison-Chirou1,
- Satoshi Inoue2,
- Richard Tomasini3,
- Isaac S. Harris2,
- Arianna Marino4,
- Massimo Federici4,
- David Dinsdale1,
- Richard A. Knight1,
- Gerry Melino1,5,6,7 and
- Tak Wah Mak2,6,7
- 1Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, United Kingdom;
- 2The Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, Toronto, Ontario M5G 2C1, Canada;
- 3Stress Cellulaire, Parc Scientifique et Technologique de Luminy, Unite 624, Institut National de la Sante et de la Recherche Medicale, Marseille 13288, France;
- 4Department of Internal Medicine, University of Rome ‘Tor Vergata,’ Rome 00133, Italy;
- 5Department of Experimental Medicine and Surgery, Biochemistry IDI-IRCCS Laboratory, University of Rome ‘Tor Vergata,’ Rome 00133, Italy
Abstract
Aging is associated with impaired scavenging of reactive oxygen species (ROS). Here, we show that TAp73, a p53 family member, protects against aging by regulating mitochondrial activity and preventing ROS accumulation. TAp73-null mice show more pronounced aging with increased oxidative damage and senescence. TAp73 deletion reduces cellular ATP levels, oxygen consumption, and mitochondrial complex IV activity, with increased ROS production and oxidative stress sensitivity. We show that the mitochondrial complex IV subunit cytochrome C oxidase subunit 4 (Cox4i1) is a direct TAp73 target and that Cox4i1 knockdown phenocopies the cellular senescence of TAp73-null cells. Results indicate that TAp73 affects mitochondrial respiration and ROS homeostasis, thus regulating aging.
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Footnotes
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↵6 These authors equally contributed to this work.
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↵7 Corresponding authors
E-mail tmak{at}uhnresearch.ca
E-mails melino{at}uniroma2.it
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.197640.112.
- Received June 1, 2012.
- Accepted July 30, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press
Freely available online through the Genes & Development Open Access option.
