CHCHD10 Modulates Thermogenesis of Adipocyte by Regulating Lipolysis

Brown and beige adipocytes dissipate energy in a non-shivering thermogenesis manner, exerting beneficial effects on metabolic homeostasis. CHCHD10 is a nuclear-encoded mitochondrial protein involved in cristae organization; however, its role in thermogenic adipocytes remains unknown. Herein, we identify CHCHD10 as a novel regulator for adipocyte thermogenesis. CHCHD10 is dramatically upregulated during thermogenic adipocytes activation by PPARγ-PGC1α, and positively correlated with UCP1 expression in the adipose tissues from human and mice. We generate adipocyte-specific Chchd10 knockout mice (Chchd10-AKO) and find that depleting CHCHD10 leads to impaired UCP1-dependent thermogenesis and energy expenditure in the fasting state, with no effect in fed state. Lipolysis in adipocytes is disrupted by CHCHD10 deficiency, while augmented lipolysis via ATGL overexpression recovers adipocyte thermogenesis in Chchd10-AKO mice. Consistently, overexpression of Chchd10 activates thermogenic adipocytes. Mechanistically, CHCHD10 deficiency results in the disorganization of mitochondrial cristae, leading to impairment of oxidative phosphorylation complex assembly in mitochondria, which in turn inhibits ATP generation. Decreased ATP results in downregulation of lipolysis by reducing nascent protein synthesis of ATGL, thereby suppressing adipocyte thermogenesis. As a result, Chchd10-AKO mice are prone to develop high-fat diet-induced metabolic disorders. Together, our findings reveal essential role of CHCHD10 in regulating lipolysis and thermogenic program in adipocytes.