A ferroptosis defense mechanism mediated by glycerol-3-phosphate dehydrogenase 2 in mitochondria
Menée à l'aide de lignées cellulaires et d'un modèle murin, cette étude met en évidence, dans les mitochondries des cellules cancéreuses, un mécanisme de défense contre la ferroptose impliquant la déshydrogénase GPD2 et la peroxydase GPX4, puis démontre que l'inactivation conjointe de ces deux enzymes par délétion génétique supprime de façon synergique la croissance tumorale
Mechanisms of defense against ferroptosis (an iron-dependent form of cell death induced by lipid peroxidation) in cellular organelles remain poorly understood, hindering our ability to target ferroptosis in disease treatment. In this study, metabolomic analyses revealed that treatment of cancer cells with glutathione peroxidase 4 (GPX4) inhibitors results in intracellular glycerol-3-phosphate (G3P) depletion. We further showed that supplementation of cancer cells with G3P attenuates ferroptosis induced by GPX4 inhibitors in a G3P dehydrogenase 2 (GPD2)-dependent manner; GPD2 deletion sensitizes cancer cells to GPX4 inhibition-induced mitochondrial lipid peroxidation and ferroptosis, and combined deletion of GPX4 and GPD2 synergistically suppresses tumor growth by inducing ferroptosis in vivo. Mechanistically, inner mitochondrial membrane-localized GPD2 couples G3P oxidation with ubiquinone reduction to ubiquinol, which acts as a radical-trapping antioxidant to suppress ferroptosis in mitochondria. Taken together, these results reveal that GPD2 participates in ferroptosis defense in mitochondria by generating ubiquinol.