title: Mitochondrial metabolites extend lifespan.
abstract: Disruption of mitochondrial respiration in the nematode Caenorhabditis elegans can extend lifespan. We previously showed that long-lived respiratory mutants generate elevated amounts of α-ketoacids. These compounds are structurally related to α-ketoglutarate, suggesting they may be biologically relevant. Here, we show that provision of several such metabolites to wild-type worms is sufficient to extend their life. At least one mode of action is through stabilization of hypoxia-inducible factor-1 (HIF-1). We also find that an α-ketoglutarate mimetic, 2,4-pyridinedicarboxylic acid (2,4-PDA), is alone sufficient to increase the lifespan of wild-type worms and this effect is blocked by removal of HIF-1. HIF-1 is constitutively active in isp-1(qm150) Mit mutants, and accordingly, 2,4-PDA does not further increase their lifespan. Incubation of mouse 3T3-L1 fibroblasts with life-prolonging α-ketoacids also results in HIF-1α stabilization. We propose that metabolites that build up following mitochondrial respiratory dysfunction form a novel mode of cell signaling that acts to regulate lifespan.
authors.affiliation: The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.|Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mishur
authors.affiliation: The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.|Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
authors.forename: Maruf
authors.initials: M
authors.lastname: Khan
authors.affiliation: The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.|Department of Cellular & Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Munkácsy
authors.affiliation: Department of Cellular & Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
authors.forename: Lokendra
authors.initials: L
authors.lastname: Sharma
authors.affiliation: Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Bokov
authors.affiliation: The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
authors.forename: Haley
authors.initials: H
authors.lastname: Beam
authors.affiliation: The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
authors.forename: Oxana
authors.initials: O
authors.lastname: Radetskaya
authors.affiliation: The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Borror
authors.affiliation: The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Lane
authors.affiliation: Department of Cellular & Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Bai
authors.affiliation: The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.|Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
authors.forename: Shane L
authors.initials: SL
authors.lastname: Rea
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism*; D008136:Longevity / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids
keywords: Caenorhabditis elegans; EGL-9/PHD; Mit mutants; aging; glutaric acidemia; hypoxia-inducible factor isp-1; hypoxia-inducible factor-1; jumonji domain-containing; metabolism; mitochondria; α-ketoglutarate-dependent hydroxylases