Petit Michele, Koziel Rafal, Etemad Solmaz, Pircher Haymo, Jansen-Dürr Pidder
Institute for Biomedical Aging Research, Universität Innsbruck, Rennweg 10, A-6020 Innsbruck, Austria.
Institute for Biomedical Aging Research, Universität Innsbruck, Rennweg 10, A-6020 Innsbruck, Austria.
Exp Gerontol. 2017 Jun;92:7-12. doi: 10.1016/j.exger.2017.03.004. Epub 2017 Mar 8.
In this study we report the identification of FAH domain containing protein 1 (FAHD1), a recently described member of the fumarylacetoacetate hydrolase (FAH) superfamily of metabolic enzymes, as a novel player in the regulation of cellular senescence. FAHD1 was found in a proteomic screen searching for mitochondrial proteins, which are differentially regulated in mitochondria from young and senescent human endothelial cells, and subsequently identified as oxaloacetate decarboxylase. We report here that depletion of FAHD1 from human endothelial cells inhibited mitochondrial energy metabolism and subsequently induced premature senescence. Whereas senescence induced by FAHD1 depletion was not associated with DNA damage, we noted a reduction of mitochondrial ATP-coupled respiration associated with upregulation of the cdk inhibitor p21. These results indicate that FAHD1 is required for mitochondrial function in human cells and provide additional support to the growing evidence that mitochondrial dysfunction can induce cellular senescence by metabolic alterations independent of the DNA damage response pathway.
在本研究中，我们报告了含富马酰乙酰乙酸水解酶（FAH）结构域蛋白1（FAHD1）的鉴定情况。FAHD1是代谢酶富马酰乙酰乙酸水解酶（FAH）超家族中最近描述的成员，是细胞衰老调控中的一个新参与者。在一项蛋白质组学筛选中发现了FAHD1，该筛选旨在寻找在年轻和衰老的人内皮细胞线粒体中差异调节的线粒体蛋白，随后将其鉴定为草酰乙酸脱羧酶。我们在此报告，从人内皮细胞中耗尽FAHD1会抑制线粒体能量代谢，并随后诱导过早衰老。虽然FAHD1耗尽诱导的衰老与DNA损伤无关，但我们注意到与细胞周期蛋白依赖性激酶（cdk）抑制剂p21上调相关的线粒体ATP偶联呼吸减少。这些结果表明，FAHD1是人类细胞线粒体功能所必需的，并为越来越多的证据提供了额外支持，即线粒体功能障碍可通过独立于DNA损伤反应途径的代谢改变诱导细胞衰老。
