Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
Division of Nutritional Sciences, Cornell University, Ithaca, NY 14850, USA.
Science. 2020 Apr 3;368(6486):54-60. doi: 10.1126/science.aay2494. Epub 2020 Mar 19.
The endoplasmic reticulum (ER) engages mitochondria at specialized ER domains known as mitochondria-associated membranes (MAMs). Here, we used three-dimensional high-resolution imaging to investigate the formation of pleomorphic "megamitochondria" with altered MAMs in brown adipocytes lacking the Sel1L-Hrd1 protein complex of ER-associated protein degradation (ERAD). Mice with ERAD deficiency in brown adipocytes were cold sensitive and exhibited mitochondrial dysfunction. ERAD deficiency affected ER-mitochondria contacts and mitochondrial dynamics, at least in part, by regulating the turnover of the MAM protein, sigma receptor 1 (SigmaR1). Thus, our study provides molecular insights into ER-mitochondrial cross-talk and expands our understanding of the physiological importance of Sel1L-Hrd1 ERAD.
内质网 (ER) 在称为线粒体相关膜 (MAMs) 的特化 ER 结构域与线粒体相互作用。在这里，我们使用三维高分辨率成像来研究在缺乏 ER 相关蛋白降解 (ERAD) 的 Sel1L-Hrd1 蛋白复合物的棕色脂肪细胞中具有改变的 MAMs 的多形性“巨大线粒体”的形成。棕色脂肪细胞中 ERAD 缺陷的小鼠对冷敏感，并表现出线粒体功能障碍。ERAD 缺陷通过调节 MAM 蛋白西格玛受体 1 (SigmaR1) 的周转来影响 ER-线粒体接触和线粒体动力学，至少在部分程度上是这样。因此，我们的研究为 ER-线粒体相互作用提供了分子见解，并扩展了我们对 Sel1L-Hrd1 ERAD 的生理重要性的理解。
