141-OR: Regulation of Mitochondrial Dynamics in Brown Adipocytes by the Endoplasmic Reticulum-Associated Degradation

Abstract

Recent studies have implicated the endoplasmic reticulum (ER) in organelle crosstalk including mitochondria; however, the underlying molecular mechanism and physiological significance remain largely unclear. Here we show that the Sel1L-Hrd1 protein complex of the most conserved ER-associated protein degradation (ERAD) in brown adipocytes is essential for cold-induced thermogenesis in part by managing mitochondrial dynamics. While largely indistinguishable from their wild type littermates, adipocyte or brown adipocyte-specific Sel1L-deficient mice are cold sensitive. Mechanistically, we found that mitochondria in Sel1L-deficient brown adipocytes are dysfunctional with a large portion of them being enlarged and becoming irregularly shaped, i.e., “megamitochondria,” as a result of attenuated fission. Moreover, Sel1L deficiency in cold-stimulated brown adipocytes alters ER-mitochondrial contact and consequently, mitochondria grow around ER tubules leading to the formation of unique intramitochondrial tubule(s). Lastly, brown adipocyte-specific Hrd1-deficient mice exhibit similar phenotypes in terms of cold sensitivity, mitochondrial morphology and dynamics, but not Ire1a- and β-adrenergic receptors-deficient mice. We conclude that Sel1L-Hrd1 ERAD in brown adipocytes is intimately involved in the regulation of mitochondrial dynamics in thermogenesis and provides exciting novel insights into the emerging field of organelle crosstalk. Disclosure Z. Zhou: None. M. Torres: None. L. Qi: None. Funding American Diabetes Association (1-19-PDF-093 to Z.Z.); National Institutes of Health