ACAT1/SOAT1 governs mitochondrial dynamics and thermogenesis via the mTOR-MFN2-USP2 axis in brown adipocytes

Mitochondrial dynamics are crucial for brown adipose tissue (BAT) thermogenesis and systemic energy homeostasis; yet, the cholesterol-sensing pathways regulating these processes remain poorly defined. Here we report that ACAT1, an endoplasmic reticulum (ER)-resident cholesterol esterase, acts as a critical rheostat of thermogenesis by governing mitochondrial dynamics in BAT. Mice with brown adipocyte-specific Acat1 deletion exhibit cold intolerance and exacerbated Western diet-induced obesity. Mechanistically, ACAT1 inhibition triggers intracellular cholesterol accu7mulation that activates mTOR-mediated phosphorylation of the mitochondrial fusion protein MFN2 at Serine 200. This modification recruits the deubiquitinase USP2, stabilizing MFN2 by inhibiting its proteasomal degradation and driving pathological mitochondrial fusion and ER-mitochondria contacts. Hence, our findings establish the ACAT1-mTOR-MFN2-USP2 axis as a fundamental mechanism coordinating cholesterol metabolism with mitochondrial dynamics, thermogenesis, and systemic energy balance, revealing its critical pathophysiological significance in obesity. Cholesterol levels must be precisely controlled in cells. Here, the authors identify the mTOR-MFN2-USP2 axis linking ACAT1-mediated cholesterol metabolism to mitochondrial homeostasis, critical for brown-fat thermogenesis and whole-body metabolism.