title: Two Conserved Histone Demethylases Regulate Mitochondrial Stress-Induced Longevity.
abstract: 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.
authors.affiliation: 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.
authors.forename: Carsten
authors.initials: C
authors.lastname: Merkwirth
authors.affiliation: Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
authors.forename: Virginija
authors.initials: V
authors.lastname: Jovaisaite
authors.affiliation: 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.
authors.forename: Jenni
authors.initials: J
authors.lastname: Durieux
authors.affiliation: Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
authors.forename: Olli
authors.initials: O
authors.lastname: Matilainen
authors.affiliation: 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.
authors.forename: Sabine D
authors.initials: SD
authors.lastname: Jordan
authors.affiliation: Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Quiros
authors.affiliation: 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.
authors.forename: Kristan K
authors.initials: KK
authors.lastname: Steffen
authors.affiliation: Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
authors.forename: Evan G
authors.initials: EG
authors.lastname: Williams
authors.affiliation: Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mouchiroud
authors.affiliation: 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.
authors.forename: Sarah U
authors.initials: SU
authors.lastname: Tronnes
authors.affiliation: The Glenn Center for Research on Aging, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Murillo
authors.affiliation: 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.
authors.forename: Suzanne C
authors.initials: SC
authors.lastname: Wolff
authors.affiliation: The Glenn Center for Research on Aging, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Reuben J
authors.initials: RJ
authors.lastname: Shaw
authors.affiliation: 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.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.affiliation: 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.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dillin
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D056466:Histone Demethylases / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D008136:Longevity; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D056811:Unfolded Protein Response
chemical_list: D029742:Caenorhabditis elegans Proteins; D014157:Transcription Factors; D056466:Histone Demethylases; C553255:JMJD-1.2 protein, C elegans; C000591647:JMJD-3.1 protein, C elegans; D056484:Jumonji Domain-Containing Histone Demethylases; C553256:PHF8 protein, mouse; C523761:Kdm6b protein, mouse