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Two Conserved Histone Demethylases Regulate Mitochondrial Stress-Induced Longevity.

  • Merkwirth C Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; The Glenn Center for Research on Aging, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; The Paul F. Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA 94720, USA.
  • Jovaisaite V Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
  • Durieux J Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; The Paul F. Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA 94720, USA.
  • Matilainen O Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
  • Jordan SD Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; The Paul F. Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • Quiros PM Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
  • Steffen KK Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; The Paul F. Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA 94720, USA.
  • Williams EG Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
  • Mouchiroud L Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
  • Tronnes SU Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; The Paul F. Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA 94720, USA.
  • Murillo V The Glenn Center for Research on Aging, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • Wolff SC Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; The Paul F. Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA 94720, USA.
  • Shaw RJ The Glenn Center for Research on Aging, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • Auwerx J Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland. Electronic address: admin.auwerx@epfl.ch.
  • Dillin A Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; The Paul F. Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: dillin@berkeley.edu.
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  • 2016-05-03
Published in:
  • Cell. - 2016
Animals
Caenorhabditis elegans
Caenorhabditis elegans Proteins
Histone Demethylases
Jumonji Domain-Containing Histone Demethylases
Longevity
Mice
Mitochondria
Transcription Factors
Transcription, Genetic
Unfolded Protein Response
English Across eukaryotic species, mild mitochondrial stress can have beneficial effects on the lifespan of organisms. Mitochondrial dysfunction activates an unfolded protein response (UPR(mt)), a stress signaling mechanism designed to ensure mitochondrial homeostasis. Perturbation of mitochondria during larval development in C. elegans not only delays aging but also maintains UPR(mt) signaling, suggesting an epigenetic mechanism that modulates both longevity and mitochondrial proteostasis throughout life. We identify the conserved histone lysine demethylases jmjd-1.2/PHF8 and jmjd-3.1/JMJD3 as positive regulators of lifespan in response to mitochondrial dysfunction across species. Reduction of function of the demethylases potently suppresses longevity and UPR(mt) induction, while gain of function is sufficient to extend lifespan in a UPR(mt)-dependent manner. A systems genetics approach in the BXD mouse reference population further indicates conserved roles of the mammalian orthologs in longevity and UPR(mt) signaling. These findings illustrate an evolutionary conserved epigenetic mechanism that determines the rate of aging downstream of mitochondrial perturbations.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/209705
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