| RRC ID |
53232
|
| 著者 |
Mishur RJ, Khan M, Munkácsy E, Sharma L, Bokov A, Beam H, Radetskaya O, Borror M, Lane R, Bai Y, Rea SL.
|
| タイトル |
Mitochondrial metabolites extend lifespan.
|
| ジャーナル |
Aging Cell
|
| 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.
|
| 巻・号 |
15(2)
|
| ページ |
336-48
|
| 公開日 |
2016-4-1
|
| DOI |
10.1111/acel.12439
|
| PMID |
26729005
|
| PMC |
PMC4783347
|
| MeSH |
3T3-L1 Cells
Animals
Caenorhabditis elegans / metabolism*
Caenorhabditis elegans Proteins / metabolism*
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Ketoglutaric Acids / metabolism*
Longevity / physiology*
Mice
Mitochondria / metabolism*
|
| IF |
7.238
|
| 引用数 |
28
|
| リソース情報 |
| 線虫 |
tm2285 |
