1959-P: Sel1l-Hrd1 ER-Associated Degradation (ERAD) Controls Mitochondrial Dynamics, ER-Mitochondrial Dynamics, and ER-Mitochondria Contacts in Brown Adipocytes

Heat generation, mediated by mitochondrial respiration in Brown Adipose Tissue (BAT), is important for defense against cold and maintenance of whole-body homeostasis. Recent works have demonstrated the presence of metabolically active BAT in adult humans, raising the prospect that augmenting brown fat abundance and/or function may provide an effective avenue for the treatment of obesity and its associated metabolic disorders. In this work, we show that the Sel1L-Hrd1 ERAD complex is essential for cold-induced thermogenesis in part by managing mitochondrial dynamics and ER-mitochondria contact in brown adipocytes. While largely indistinguishable from their wildtype littermates, adipocyte-specific Sel1L-deficient mice are cold sensitive associated with mitochondrial dysfunction. Using a combination of transmission electron microscopy (TEM), high-resolution three-dimensional (3D) imaging techniques such as Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) and Serial Block-face Scanning Electron Microscopy (SBEM), revealed that mitochondria in Sel1L-deficient brown adipocytes are dramatically enlarged and polymorphic in response to acute cold challenge. Strikingly, mitochondria in Sel1L-deficient brown adipocytes exhibit increased interaction with ER tubules leading to the formation of unique intramitochondrial tubule(s). Lastly, Sel1L affects mitochondrial biology as a part of the Hrd1 ERAD complex, as adipocyte-specific Hrd1-deficient mouse, phenocopy Sel1L-deficient mice in terms of mitochondrial phenotype. Hence, our data provide novel molecular insights and platform for future studies into ER-mitochondrial interaction and position Sel1L-Hrd1 ERAD at the center of organelle crosstalk. Disclosure M. Torres: None. Z. Zhou: None. L. Qi: None. S. Wang: None. Funding National Institutes of Health (1R35GM130292)