Mitochondrial ROS-induced metabolic alterations differentially regulate ferroptosis vulnerability of hepatocytes.

Abstract

Ferroptosis is an iron-catalyzed lipid peroxidation (LP)-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, redox state, and ferroptosis vulnerability of the hepatocytes was investigated by utilizing mtROS inducers, including iron overload and pharmacological inducers. Elevations in mtROS production and LP suppressed glycolysis, fatty acid oxidation, and tricarboxylic acid (TCA) cycle activity, protecting hepatocytes from ferroptosis. In contrast, mtROS-induced signaling downregulated 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 downregulation of CoQ8A is dependent on farnesoid X receptor (FXR) and retinoid X receptors (RXRs). Collectively, these findings suggest that mtROS induces downregulation of glutathione and CoQ biosynthesis, thereby promoting ferroptotic death in hepatocytes.