Ferroptosis 세포사의 분자적 메커니즘 연구

Abstract

Ferroptosis is a novel form of programmed cell death in which the accumulation of intracellular iron promotes lipid peroxidation, leading to cell death. Recently, the induction of autophagy has been suggested during ferroptosis. However, this relationship between autophagy and ferroptosis is still controversial and the autophagy-inducing mediator remains unknown. In this study, Furthermore, autophagy leads to iron-dependent ferroptosis by degradation of ferritin and induction of transferrin receptor 1 (TfR1) expression, in wild-type and autophagy-deficient cells, BECN1+/− and LC3B−/−. Consistently, autophagy deficiency caused depletion of intracellular iron and reduced lipid peroxidation, resulting in cell survival during erastin-induced ferroptosis. Moreover, autophagy was triggered by erastin-induced reactive oxygen species (ROS) in ferroptosis. These data provide evidence that ROS-induced autophagy is a key regulator of ferritin degradation and TfR1 expression during ferroptosis. These results contributes that toward our understanding of the ferroptotic processes and also helps resolve some of the controversies associated with this phenomenon. |Ferroptosis is a novel form of regulated cell death, characterized by an iron-dependent increase in lipid peroxidation. In the aspect of iron metabolism, mitochondria play a key role. Ferroptosis was characterized by condensed mitochondrial membrane densities and smaller volume than normal mitochondria. PGC1α is the master regulator of mitochondrial biogenesis. However, relationship between PGC1α and ferroptosis remains has not been studied yet. In this study, the role of PGC1α was investigated in ferroptosis. The expression of PGC1α was increased by the ferroptosis inducer, erastin. Furthermore, PGC1α inhibitor suppresses erastin-induced cell death. The most important biochemical features of ferroptosis are the elevated levels of lipid hydroperoxides (LOOH) and ferrous ion (Fe2+) concentration. Thus, erastin-triggered lipid peroxidation and intracellular levels of ferrous ion were regulated by PGC1α inhibitor in HT1080 fibrosarcoma cells. And this phenomenon was the equal in PGC1α shRNA transfected HT1080 cells. Moreover, PGC1α was triggered by erastin-induced mitochondria dysfunction during ferroptosis. Erastin-induced mitochondria dysfunction such as loss of mitochondria membrane potential and mitochondrial ROS production, was blocked in PGC1α inhibition. Previously, HO-1 is known as an essential enzyme in the iron-dependent lipid peroxidation during ferroptosis. In the present study, HO-1 induced by ferroptosis is regulated by PGC1α. Taken together these results suggested that PGC1α is an essential for erastin-induced mitochondria dysfunction during ferroptotic cancer cell death.