Mitochondrial ROS induces metabolic adaptations and maladaptations that differentially regulate ferroptosis sensitivity of the hepatocytes

Ferroptosis mediates the pathogenesis of a plethora of diseases. Mitochondrial reactive oxygen species (mtROS) plays a critical role in ferroptosis induction, but the precise mechanism by which mtROS promotes lipid peroxidation-dependent ferroptosis remains poorly understood. Herein, we employed hepatocytes and iron-induced ferroptosis as models to identify the specific mtROS-mediated redox and metabolic changes that modulate ferroptosis sensitivity. Iron overload induced the activation of multiple antioxidative mechanisms, including altered transport and metabolism of redox-active metals, small Maf (sMaf)-mediated activation of transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), and an increased potential of glutathione biosynthesis. Iron also induced mtROS-dependent suppression of fatty acid oxidation, the activities of citric acid cycle and mitochondrial respiration, protecting against ferroptosis. We further identified that mtROS signaling potentially impairs the biosynthesis of coenzyme Q10 (CoQ) by attenuating the expression of genes in the mevalonate pathway and CoQ8A, a stabilizer of CoQ complex. Importantly, elevating CoQ8A expression mitigated, whereas silencing CoQ8A expression enhanced, the vulnerability of hepatocytes to ferroptosis. The mtROS-mediated downregulation of CoQ8A was dependent on farnesoid X receptor (FXR) and retinoid X receptors (RXRs). Our study demonstrated, for the first time, that mtROS induces impaired CoQ biosynthesis as a maladaptive change that promotes ferroptosis.