Mitochondrial metabolites extend lifespan |
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| Authors: | Lokendra Sharma Alex Bokov Haley Beam Oxana Radetskaya Megan Borror Rebecca Lane Yidong Bai Shane L. Rea |
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| Affiliation: | 1. Department of Cellular & Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;2. Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;3. The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;4. Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA |
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| 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. |
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| Keywords: | α ‐ketoglutarate‐dependent hydroxylases aging
Caenorhabditis elegans
EGL‐9/PHD glutaric acidemia hypoxia‐inducible factor‐1 hypoxia‐inducible factor isp‐1 jumonji domain‐containing metabolism Mit mutants mitochondria |
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