Research Article

Endoplasmic reticulum–associated degradation regulates mitochondrial dynamics in brown adipocytes

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Science  03 Apr 2020:
Vol. 368, Issue 6486, pp. 54-60
DOI: 10.1126/science.aay2494

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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

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.

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