A ferroptosis defense mechanism mediated by glycerol-3-phosphate dehydrogenase 2 in mitochondria

Shiqi Wu, Chao Mao, Lavanya Kondiparthi, Masha V. Poyurovsky, Kellen Olszewski, Boyi Gan

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere2121987119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number26
DOIs
StatePublished - Jun 28 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • cell death
  • ferroptosis
  • GPD2
  • lipid peroxidation
  • mitochondria

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