Mitochondrial Reactive Oxygen Species-Induced Metabolic Alterations Differentially Regulate Ferroptosis Vulnerability of Hepatocytes.

Ferroptosis is an iron-catalyzed lipid peroxidation-dependent cell death that mediates the development of many diseases, including liver injury. Compelling evidence has suggested a crucial role of mitochondrial reactive oxygen species (mtROS) in the induction of ferroptosis, but the underlying mechanism remains poorly defined. In this study, the impact of mtROS-driven signaling on cellular metabolism, oxidation-reduction state, and ferroptosis vulnerability of the hepatocytes was investigated by using mtROS inducers, including iron overload and pharmacologic inducers. Elevations in mtROS production and lipid peroxidation suppressed glycolysis, fatty acid oxidation, and tricarboxylic acid cycle activity, protecting hepatocytes from ferroptosis. In contrast, mtROS-induced signaling down-regulated genes involved in glutathione biosynthesis, and coenzyme Q10 (CoQ) biosynthesis, including those in the mevalonate pathway, and CoQ8A, a key stabilizer of the CoQ biosynthetic complex. Importantly, silencing CoQ8A expression enhanced, whereas overexpression of CoQ8A reduced, ferroptosis susceptibility of the hepatocytes. Further analysis showed that mtROS-mediated down-regulation of CoQ8A is dependent on farnesoid X receptor and retinoid X receptor. Collectively, these findings suggest that mtROS induces down-regulation of glutathione and CoQ biosynthesis, thereby promoting ferroptotic death in hepatocytes.