The Mitochondrial Unfolded Protein Response Protects against Anoxia in Caenorhabditis elegans.
The Mitochondrial Unfolded Protein Response Protects against Anoxia in Caenorhabditis elegans.
复制标题
DOI：
10.1371/journal.pone.0159989
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Nehrke K
中科院分区：
文献类型：
--
作者：
Peña S;Sherman T;Brookes PS;Nehrke K
线粒体未折叠蛋白反应 (UPRmt) 是一种保护细胞“动力室”蛋白质稳态的监视途径。 UPRmt 的激活可防止活性氧、呼吸链缺陷和病理细菌造成的压力。与 UPRmt 在适应中的作用一致，我们发现溴化乙锭 (EtBr) 或线粒体 AAA 蛋白酶 spg-7 的 RNAi 对其药理学或遗传激活足以减少基于缺氧的线虫缺血再灌注损伤模型的死亡。 UPRmt 特异性转录因子 atfs-1 对于保护是必需的，并且 atfs-1 功能获得 (gf) 突变体受到内源性保护，免于死亡和功能障碍。当 UPRmt 预激活时，非致命性缺氧再灌注 (A-R) 后神经元表现出较少的轴突变性，这与线粒体应激导致细胞非自主（即“远程”）效应的概念一致，我们发现神经元中 UPRmt 的限制激活减少了 A-R 死亡。然而，atfs-1（gf）突变体在神经元中的表达导致神经元UPRmt的强烈激活，但并没有上调远端组织中的UPRmt，也没有保护线虫免受A-R毒性。这些发现表明，远程信号传导需要在事实上的线粒体应激下游发挥作用的额外成分。
The mitochondrial unfolded protein response (UPRmt) is a surveillance pathway that defends proteostasis in the “powerhouse” of the cell. Activation of the UPRmt protects against stresses imposed by reactive oxygen species, respiratory chain deficits, and pathologic bacteria. Consistent with the UPRmt’s role in adaption, we found that either its pharmacological or genetic activation by ethidium bromide (EtBr) or RNAi of the mitochondrial AAA-protease spg-7 was sufficient to reduce death in an anoxia-based Caenorhabditis elegans model of ischemia-reperfusion injury. The UPRmt-specific transcription factor atfs-1 was necessary for protection and atfs-1 gain-of-function (gf) mutants were endogenously protected from both death and dysfunction. Neurons exhibited less axonal degeneration following non-lethal anoxia-reperfusion (A-R) when the UPRmt was pre-activated, and consistent with the concept of mitochondrial stress leading to cell non-autonomous (ie. “remote”) effects, we found that restricted activation of the UPRmt in neurons decreased A-R death. However, expression of the atfs-1(gf) mutant in neurons, which resulted in a robust activation of a neuronal UPRmt, did not upregulate the UPRmt in distal tissues, nor did it protect the worms from A-R toxicity. These findings suggest that remote signaling requires additional component(s) acting downstream of de facto mitochondrial stress.