PGC1α is a key regulator of erastin-induced mitochondrial dysfunction during ferroptotic cell death

Abstract

A type of programmed cell death called ferroptosis is defined byincreased iron-dependent lipid peroxidation. Mitochondria play acentral role in iron metabolism. Mitochondrial defects includedecreased cristae density, membrane rupture, and decreasedmitochondrial membrane density, which occur as a result offerroptosis. One of the important regulator of mitochondrialbiogenesis is PGC1α. While recent studies have begun to explorethe association between PGC1α and ferroptosis, the specific role ofPGC1α in erastin-induced mitochondrial dysfunction duringferroptotic cell death has not been fully elucidated. In this study, wedemonstrate for the first time that PGC1α is a key regulator oferastin-induced mitochondrial-dependent lipid peroxidation anddysfunction during ferroptosis in HT1080 fibrosarcoma cells. In thisstudy, we examined PGC1α function in ferroptosis. Erastin, aninducer of ferroptosis, boosted the expression of PGC1α. Moreover,PGC1α down-regulation reduced erastin-induced ferroptosis. Themost important biochemical feature of ferroptosis is the increase iniron ion (Fe2＋)-dependent lipid peroxide (LOOH) concentration. Mitochondrial-dependent lipid peroxidation was abolished byPGC1α downregulation. In addition, PGC1α was induced duringmitochondrial dysfunction in erastin-induced ferroptosis. Mitochondrialmembrane potential loss and mitochondrial ROS productionassociated with erastin-induced mitochondrial dysfunction wereblocked by PGC1α inhibition. In addition, erastin-induced lipidperoxidation in HT1080 fibrosarcoma cells was regulated by PGC1inhibitor. This phenomenon was also consistent in HT1080 cellstransfected with PGC1α shRNA. Taken together, these resultssuggest that PGC1α is a key factor in erastin-induced mitochondrial-dependent lipid peroxidation and dysfunction during ferroptosiscell death.