Endoplasmic reticulum-associated degradation regulates mitochondrial dynamics in brown adipocytes.
Authors: Zhou Z;Torres M;Sha H;Halbrook CJ;Van den Bergh F;Reinert RB;Yamada T;Wang S;Luo Y;Hunter AH;Wang C;Sanderson TH;Liu M;Taylor A;Sesaki H;Lyssiotis CA;Wu J;Kersten S;Beard DA;Qi L
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
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 Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, 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.
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, 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 Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA.,Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI 48105, 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.
Biomedical Research Core Facilities, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, 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.
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA.,Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Nutrition, Metabolism and Genomics group, Wageningen University, Wageningen, Netherlands.
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA. lingq@med.umich.edu.,Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
Abstract
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.
GrantID: R01 DK120047, Acronym: DK, Agency: NIDDK NIH HHS, Country: United States | GrantID: R01 NS038619, Acronym: NS, Agency: NINDS NIH HHS, Country: United States | GrantID: R35 GM130292, Acronym: GM, Agency: NIGMS NIH HHS, Country: United States | GrantID: R01 GM113188, Acronym: GM, Agency: NIGMS NIH HHS, Country: United States | GrantID: UL1 TR000433, Acronym: TR, Agency: NCATS NIH HHS, Country: United States | GrantID: R01 GM123266, Acronym: GM, Agency: NIGMS NIH HHS, Country: United States | GrantID: U24 DK097153, Acronym: DK, Agency: NIDDK NIH HHS, Country: United States | GrantID: R01 DK107583, Acronym: DK, Agency: NIDDK NIH HHS, Country: United States | GrantID: R01 DK105393, Acronym: DK, Agency: NIDDK NIH HHS, Country: United States | GrantID: F32 CA228328, Acronym: CA, Agency: NCI NIH HHS, Country: United States | GrantID: P30 DK034933, Acronym: DK, Agency: NIDDK NIH HHS, Country: United States | GrantID: P20 GM121176, Acronym: GM, Agency: NIGMS NIH HHS, Country: United States | GrantID: R01 NS076715, Acronym: NS, Agency: NINDS NIH HHS, Country: United States | GrantID: R01 HL144657, Acronym: HL, Agency: NHLBI NIH HHS, Country: United States | GrantID: P30 AR069620, Acronym: AR, Agency: NIAMS NIH HHS, Country: United States | GrantID: R01 DK110439, Acronym: DK, Agency: NIDDK NIH HHS, Country: United States | GrantID: L30 CA231806, Acronym: CA, Agency: NCI NIH HHS, Country: United States | GrantID: K99 CA241357, Acronym: CA, Agency: NCI NIH HHS, Country: United States