Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis

Coenzyme Q (CoQ) is essential for mitochondrial respiration and required for thermogenic activity in brown adipose tissues (BAT). CoQ deficiency leads to a wide range of pathological manifestations, but mechanistic consequences of CoQ deficiency in specific tissues, such as BAT, remain poorly understood. Here, we show that pharmacological or genetic CoQ deficiency in BAT leads to stress signals causing accumulation of cytosolic mitochondrial RNAs and activation of the eIF2 alpha kinase PKR, resulting in activation of the integrated stress response (ISR) with suppression of UCP1 but induction of FGF21 expression. Strikingly, despite diminished UCP1 levels, BAT CoQ deficiency displays increased whole-body metabolic rates at room temperature and thermoneutrality resulting in decreased weight gain on high-fat diets (HFD). In line with enhanced metabolic rates, BAT and inguinal white adipose tissue (iWAT) interorgan crosstalk caused increased browning of iWAT in BAT-specific CoQ deficient animals. This mitohormesis-like effect depends on the ATF4-FGF21 axis and BAT-secreted FGF21, revealing an unexpected role for CoQ in the modulation of whole-body energy expenditure with wide-ranging implications for primary and secondary CoQ deficiencies. How changes in levels of mitochondrial electron transport chain component coenzyme Q (CoQ) affects systemic metabolism remains poorly understood. Here CoQ deficiency in brown adipose tissue (BAT) is shown to activate mitochondrial stress signaling, white adipose tissue browning and whole-body respiration.Depletion of CoQ in BAT triggers the mitochondrial unfolded protein response and integrated stress response. BAT CoQ deficiency results in cytosolic accumulation of mitochondrial RNA, leading to PKR activation, ATF4 induction and, as a result, UCP1 suppression. FGF21 secretion from CoQ-deficient BAT influences whole-body metabolism, culminating in the metabolic remodeling of inguinal white adipose tissue. The ATF4-FGF21 axis in BAT elicits mitohormetic protective responses in peripheral tissues and metabolic adaptation to BAT CoQ deficiency. Adipose tissue browning and enhanced whole-body respiration are systemic consequences of coenzyme Q depletion and resulting mitochondrial stress signaling.