@article{574fd9757024463e813c5317f9bb64f3,
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.",
keywords = "Aging, Caenorhabditis elegans, EGL-9/PHD, Glutaric acidemia, Hypoxia-inducible factor isp-1, Hypoxia-inducible factor-1, Jumonji domain-containing, Metabolism, Mit mutants, Mitochondria, α-ketoglutarate-dependent hydroxylases",
author = "Mishur, {Robert J.} and Maruf Khan and Erin Munk{\'a}csy and Lokendra Sharma and Alex Bokov and Haley Beam and Oxana Radetskaya and Megan Borror and Rebecca Lane and Yidong Bai and Rea, {Shane L.}",
note = "Funding Information: Mass spectrometry and NMR analyses were conducted at the Institutional Mass Spectrometry and NMR Laboratories at the University of Texas Health Science Center, San Antonio (UTHSCSA). Several strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). Technical support was provided by Meghan Cain. We thank Drs. Alfred Fisher (UTHSCSA), Milena Girotti (UTHSCSA) and Greg Macleod (Florida Atlantic University) for critical suggestions regarding the manuscript. Financial support was provided by the Ellison Medical Foundation (AGNS- 051908, SLR), the NIH [AG-047561 (SLR), T32 AG021890 (EM), an NRSA fellowship to RJM, and GM-109434 (YB)], and the Glenn Foundation for Medical Research (EM). Funding sources had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. Funding Information: Mass spectrometry and NMR analyses were conducted at the Institutional Mass Spectrometry and NMR Laboratories at the University of Texas Health Science Center, San Antonio (UTHSCSA). Several strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). Technical support was provided by Meghan Cain. We thank Drs. Alfred Fisher (UTHSCSA), Milena Girotti (UTHSCSA) and Greg Macleod (Florida Atlantic University) for critical suggestions regarding the manuscript. Financial support was provided by the Ellison Medical Foundation (AGNS- 051908, SLR), the NIH [AG-047561 (SLR), T32 AG021890 (EM), an NRSA fellowship to RJM, and GM-109434 (YB)], and the Glenn Foundation for Medical Research (EM). Funding sources had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. ",
year = "2016",
month = apr,
day = "1",
doi = "10.1111/acel.12439",
language = "English (US)",
volume = "15",
pages = "336--348",
journal = "Aging Cell",
issn = "1474-9718",
publisher = "Wiley-Blackwell",
number = "2",
}