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.


Z. Zhou: None. M. Torres: None. L. Qi: None.


American Diabetes Association (1-19-PDF-093 to Z.Z.); National Institutes of Health

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