Endoplasmic reticulum–associated degradation regulates mitochondrial dynamics in brown adipocytes,Science

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Endoplasmic reticulum–associated degradation regulates mitochondrial dynamics in brown adipocytes
Science ( IF 56.9 ) Pub Date : 2020-03-19 , DOI: 10.1126/science.aay2494
Zhangsen Zhou ₁ , Mauricio Torres ₁ , Haibo Sha ₂ , Christopher J Halbrook ₁ , Françoise Van den Bergh ₁ , Rachel B Reinert ₃ , Tatsuya Yamada ₄ , Siwen Wang ₁ , Yingying Luo ₁ , Allen H Hunter ₅ , Chunqing Wang ₆ , Thomas H Sanderson _{1,

7} , Meilian Liu ₆ , Aaron Taylor ₈ , Hiromi Sesaki ₄ , Costas A Lyssiotis _{1,

9,

10} , Jun Wu _{1,

11} , Sander Kersten ₁₂ , Daniel A Beard ₁ , Ling Qi _{1,

3}

Affiliation

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.
Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
College of Engineering and Michigan Center for Materials Characterization, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Biochemistry and Molecular Biology and Autophagy, Inflammation and Metabolism Center for Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
Biomedical Research Core Facilities, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Nutrition, Metabolism and Genomics group, Wageningen University, Wageningen, Netherlands.

Organelle cross-talk Endoplasmic reticulum (ER)–associated degradation (ERAD) is a quality control mechanism that allows for targeted degradation of proteins in the ER. Zhou et al. found that a particular protein complex in ERAD, Sel1L-Hrd1, regulates the dynamics of another organelle, the mitochondrion, by altering ER-mitochondria contacts. Three-dimensional high-resolution imaging in brown adipocytes from cold-challenged mice revealed that defective ERAD led to the formation of enlarged and abnormally shaped mitochondria with perforating ER tubules. The authors explored the consequences of ERAD deficiency on mitochondrial function and thermogenesis, which provides insights into ERADmediated ER-mitochondrial cross-talk and advances our understanding of the physiological importance of interorganelle contact. Science, this issue p. 54 A regulatory mechanism underlying endoplasmic reticulum–mitochondria communication is dissected in mouse fat cells. 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.

中文翻译：

内质网相关降解调节棕色脂肪细胞的线粒体动力学

细胞器串扰内质网 (ER) 相关降解 (ERAD) 是一种质量控制机制，可实现 ER 中蛋白质的靶向降解。周等人。发现 ERAD 中的一种特定蛋白质复合物 Sel1L-Hrd1 通过改变 ER-线粒体接触来调节另一种细胞器线粒体的动力学。来自冷攻击小鼠的棕色脂肪细胞的三维高分辨率成像显示，有缺陷的 ERAD 导致形成具有穿孔 ER 小管的增大且形状异常的线粒体。作者探讨了 ERAD 缺乏对线粒体功能和产热的影响，这提供了对 ERAD 介导的 ER-线粒体串扰的见解，并促进了我们对细胞器间接触生理重要性的理解。科学，这个问题 p。54 在小鼠脂肪细胞中剖析了内质网-线粒体通讯的调控机制。内质网 (ER) 在称为线粒体相关膜 (MAM) 的专门 ER 域与线粒体结合。在这里，我们使用三维高分辨率成像来研究在缺乏内质网相关蛋白降解 (ERAD) 的 Sel1L-Hrd1 蛋白复合物的棕色脂肪细胞中形成具有改变的 MAM 的多形性“巨线粒体”。棕色脂肪细胞中 ERAD 缺乏的小鼠对冷敏感并表现出线粒体功能障碍。ERAD 缺乏影响 ER-线粒体接触和线粒体动力学，至少部分是通过调节 MAM 蛋白 sigma 受体 1 (SigmaR1) 的更新。因此，

更新日期：2020-03-19

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