CoQ imbalance drives reverse electron transport to disrupt liver metabolism.

Mitochondrial reactive oxygen species (mROS) are central to physiology(1,2). Excess mROS production has been associated with several disease states(2,3); however, the precise sources, regulation and mechanism of generation in vivo remain unclear, which limits translational efforts. Here we show that in obesity, hepatic coenzyme Q (CoQ) synthesis is impaired, which increases the CoQH(2) to CoQ (CoQH(2)/CoQ) ratio and drives excessive mROS production through reverse electron transport (RET) from site I(Q) in complex I. Using multiple complementary genetic and pharmacological models in vivo, we demonstrate that RET is crucial for metabolic health. In patients with steatosis, the hepatic CoQ biosynthetic program is also suppressed, and the CoQH(2)/CoQ ratio positively correlates with disease severity. Our data identify a highly selective mechanism for pathological mROS production in obesity, which can be targeted to protect metabolic homeostasis.