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

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.