Mishur Robert J, Khan Maruf, Munkácsy Erin, Sharma Lokendra, Bokov Alex, Beam Haley, Radetskaya Oxana, Borror Megan, Lane Rebecca, Bai Yidong, Rea Shane L
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.
Aging Cell. 2016 Apr;15(2):336-48. doi: 10.1111/acel.12439. Epub 2016 Jan 5.
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.
线虫秀丽隐杆线虫中线粒体呼吸的破坏可以延长寿命。我们之前表明，长寿的呼吸突变体产生的α-酮酸量增加。这些化合物在结构上与α-酮戊二酸相关，表明它们可能具有生物学相关性。在这里，我们表明向野生型线虫提供几种这样的代谢物足以延长它们的寿命。至少一种作用方式是通过稳定缺氧诱导因子-1（HIF-1）。我们还发现，一种α-酮戊二酸模拟物2,4-吡啶二甲酸（2,4-PDA）单独就足以增加野生型线虫的寿命，并且这种作用被去除HIF-1所阻断。HIF-1在isp-1（qm150）线粒体突变体中组成性激活，因此，2,4-PDA不会进一步增加它们的寿命。用延长寿命的α-酮酸孵育小鼠3T3-L1成纤维细胞也会导致HIF-1α稳定。我们提出，线粒体呼吸功能障碍后积累的代谢物形成了一种新的细胞信号传导模式，其作用是调节寿命。
