Although the given name “ferroptosis” focuses on the critical role of iron, the involvement of GPx4, reduced glutathione (GSH), and α-tocopherol entails lipid peroxidation as the molecular mechanism executing the death sentence. 1) led to identifying a sub-routine of programmed death ( 37), and because inhibitors of neither apoptosis nor necroptosis can rescue GPx4-depleted cells, the claim of having identified a novel mechanism seems appropriate. Indeed, the phenotype resulting from GPx4 silencing or inhibition ( Fig. Since a comprehensive review on biochemistry and molecular biology of GPx4 has been recently published ( 69), this review will specifically focus on the relationship between GPx4, iron-dependent lipid peroxidation, and cell death. T he selenoperoxidase glutathione peroxidase 4 ( GPx4), discovered in 1982 as a cytosolic “peroxidation inhibiting protein” ( 110), is seen today as a specific target of new pharmacological treatments aiming at activating or inhibiting cell death in cancer or degenerative diseases, respectively ( 36, 123). This is expected to drive drug discovery that is aimed at halting cell death in degenerative diseases or boosting it in cancer cells. Also, unknown are the molecules eventually killing cells and the mechanisms underlying the drop of the cellular anti-peroxidant capacity.įuture Directions: Molecular events and mechanisms of ferroptosis to be unraveled and validated on animal models are GPx4 inactivation, role of GSH concentration, increased iron availability, and membrane structure and composition. The basic mechanism of ferroptosis, therefore, fits the features of activation of lipid peroxidation.Ĭritical Issues: Still lacking are convincing proofs that lipoxygenases are involved in ferroptosis. Ferroptosis induction may underlie spontaneous human diseases, such as major neurodegeneration and neuroinflammation, causing an excessive cell death. Recent Advances: Ferroptosis has been recently identified as a cell death subroutine that is specifically activated by missing GPx4 activity and inhibited by iron chelation or α-tocopherol supplementation. Thus, GPx4, GSH, and α-tocopherol are integrated in a concerted anti-peroxidant mechanism. α-Tocopherol both specifically breaks peroxidative chain propagation and inhibits lipoxygenases. PLOOH is both a product and the major initiator of peroxidative chain reactions, as well as an activator of lipoxygenases. It is specifically prevented by glutathione peroxidase 4 (GPx4), the selenoenzyme that reduces PLOOH by glutathione (GSH). Significance: Iron-dependent lipid peroxidation is a complex oxidative process where phospholipid hydroperoxides (PLOOH) are produced in membranes and finally transformed into a series of decomposition products, some of which are endowed with biological activity.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. Archives
March 2023
Categories |