Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.
Functional Proteomics, SFB 815 Core Unit, Goethe-University Frankfurt, Frankfurt, Germany.
Cell Mol Life Sci. 2018 Aug;75(16):3051-3067. doi: 10.1007/s00018-018-2779-y. Epub 2018 Feb 20.
Cell stress such as hypoxia elicits adaptive responses, also on the level of mitochondria, and in part is mediated by the hypoxia-inducible factor (HIF) 1α. Adaptation of mitochondria towards acute hypoxic conditions is reasonably well understood, while regulatory mechanisms, especially of respiratory chain assembly factors, under chronic hypoxia remains elusive. One of these assembly factors is transmembrane protein 126B (TMEM126B). This protein is part of the mitochondrial complex I assembly machinery. We identified changes in complex I abundance under chronic hypoxia, in association with impaired substrate-specific mitochondrial respiration. Complexome profiling of isolated mitochondria of the human leukemia monocytic cell line THP-1 revealed HIF-1α-dependent deficits in complex I assembly and mitochondrial complex I assembly complex (MCIA) abundance. Of all mitochondrial MCIA members, we proved a selective HIF-1-dependent decrease of TMEM126B under chronic hypoxia. Mechanistically, HIF-1α induces the E3-ubiquitin ligase F-box/WD repeat-containing protein 1A (β-TrCP1), which in turn facilitates the proteolytic degradation of TMEM126B. Attenuating a functional complex I assembly appears critical for cellular adaptation towards chronic hypoxia and is linked to destruction of the mitochondrial assembly factor TMEM126B.
细胞应激，如缺氧，会引发适应性反应，这也表现在线粒体水平上，部分是由缺氧诱导因子 (HIF) 1α介导的。对于急性缺氧条件下线粒体的适应机制已经有了相当的了解，而慢性缺氧下的调节机制，特别是呼吸链组装因子的调节机制，仍然难以捉摸。这些组装因子之一是跨膜蛋白 126B (TMEM126B)。这种蛋白质是线粒体复合物 I 组装机制的一部分。我们发现，在慢性缺氧下，TMEM126B 的含量发生了变化，这与底物特异性线粒体呼吸受损有关。人类白血病单核细胞系 THP-1 分离线粒体的复合物组学分析显示，HIF-1α 依赖性复合物 I 组装和线粒体复合物 I 组装复合物 (MCIA) 丰度降低。在所有的线粒体 MCIA 成员中，我们证明了 TMEM126B 在慢性缺氧下存在选择性的 HIF-1 依赖性减少。从机制上讲，HIF-1α 诱导 E3 泛素连接酶 F-box/WD 重复蛋白 1A (β-TrCP1)，进而促进 TMEM126B 的蛋白水解降解。减弱功能性复合物 I 组装似乎对细胞适应慢性缺氧至关重要，并与线粒体组装因子 TMEM126B 的破坏有关。
