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Title: Two Conserved Histone Demethylases Regulate Mitochondrial Stress-Induced Longevity.

Authors: Merkwirth, Carsten; Jovaisaite, Virginija; Durieux, Jenni; Matilainen, Olli; Jordan, Sabine D; Quiros, Pedro M; Steffen, Kristan K; Williams, Evan G; Mouchiroud, Laurent; Tronnes, Sarah U; Murillo, Virginia; Wolff, Suzanne C; Shaw, Reuben J; Auwerx, Johan; Dillin, Andrew

Published In Cell, (2016 May 19)

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.

PubMed ID: 27133168 Exiting the NIEHS site

MeSH Terms: Animals; Caenorhabditis elegans Proteins/metabolism*; Caenorhabditis elegans/genetics; Caenorhabditis elegans/physiology*; Histone Demethylases/metabolism*; Jumonji Domain-Containing Histone Demethylases/metabolism*; Longevity; Mice; Mitochondria/metabolism; Transcription Factors/metabolism; Transcription, Genetic; Unfolded Protein Response

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Last Reviewed: October 07, 2024