Repression of ferroptotic cell death by mitochondrial calcium signaling.

ABSTRACT: The uptake of Ca²⁺ into and extrusion of calcium from the mitochondrial matrix, regulated by the mitochondrial Ca²⁺ uniporter (MCU), is a fundamental biological process that has crucial impacts on cellular metabolism, signaling, growth and survival. Herein, we report that the embryonic lethality of Mcu-deficient mice is fully rescued by orally supplementing ferroptosis inhibitor lipophilic antioxidant vitamin E and ubiquinol. Mechanistically, we found MCU promotes acetyl-CoA-mediated GPX4 acetylation at K90 residue, and K90R mutation impaired the GPX4 enzymatic activity, a step that is crucial for ferroptosis. Structural analysis supports the possibility that GPX4 K90R mutation alters the conformational state of the molecule, resulting in disruption of a salt b

SUBMITTER: Chen J 

PROVIDER: S-EPMC10371111 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature