Mitochondrial phosphoenolpyruvate carboxykinase 2 counteracts ferroptosis via catalytic activity independent of mitochondrial stress

Ferroptosis is a recently identified form of programmed cell death. Increasing studies have suggested the intricate regulation of Ferroptosis by metabolic pathways. However, whether gluconeogenesis, a critical branch of glucose metabolism maintaining the dynamic equilibrium with glycolysis, could modulate Ferroptosis, remains to be elucidated. Herein, we reported that ferroptotic stress facilitates the expressions of gluconeogenic genes, especially Phosphoenolpyruvate carboxykinase 2 (PCK2). Importantly, ablation of PCK2 substantially enhances Ferroptosis susceptibility. This pro-ferroptotic effect is partially attributed to the decreased phosphoenolpyruvate production and occurs independently of mitochondrial stress. Notably, ectopic expression of cytosolic Phosphoenolpyruvate carboxykinase 1 (PCK1) fails to mitigate Ferroptosis during PCK2 depletion, suggesting a distinct Ferroptosis regulation between PCK1 and PCK2. Therefore, this study highlights a novel Ferroptosis regulation by gluconeogenesis, and PCK2 is a potent anti-ferroptotic molecule, although the detailed mechanism remains to be dissected.

Ferroptosis; Gluconeogenesis; Lipid peroxidation; Mitochondria; PCK2.