期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2121987119
关键词
GPD2; ferroptosis; mitochondria; lipid peroxidation; cell death
资金
- University of Texas MD Anderson Cancer Center
- Cancer Prevention & Research Institute of Texas Grant from the National Institutes of Health [RP220258, R01CA181196, R01CA244144, R01CA247992]
- National Institutes of Health Cancer Center Support Grant [P30CA016672]
- Emerson Collective Cancer Research Fund
This study reveals the mechanism of GPD2 in defense against ferroptosis, suppressing mitochondrial ferroptosis by generating ubiquinol. This finding provides a new avenue for targeting ferroptosis in disease treatment.
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.
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