Ferroptosis is associated with oxygen-glucose deprivation/reoxygenation-induced Sertoli cell death

Abstract

Sertoli cell death contributes to spermatogenesis impairment, which is associated with male infertility. Testicular ischemia‑reperfusion (I/R) injury induces the cell death of germ cells and Sertoli cells, whereas inhibition of cell death ameliorates acute testicular I/R damage. The aim of the present study was to investigate the mechanism of I/R stress-induced cell death in TM4 cells. Oxygen‑glucose deprivation and reoxygenation (OGD/R) was demonstrated to induce I/R injury and cell death in TM4 cells. Cell death was blocked by the reactive oxygen species (ROS) inhibitor N‑acetylcysteine, as well as lipid peroxidation inhibitors Liproxstatin‑1 and iron chelator deferoxamine; however, inhibitors of apoptosis, necrosis or autophagy had no effect. It was also demonstrated that iron and lipid ROS levels were elevated in I/R injury and that mitochondria decreased in size and increased in membrane density, which is indicative of ferroptosis. Furthermore, the generation of lipid ROS suggests iron accumulation and glutathione (GSH) depletion. The expression of ferroportin (Fpn) protein and mRNA was decreased in TM4 cells. Notably, overexpression of Fpn inhibited ferroptosis, lipid ROS generation and iron accumulation. In addition, GSH‑dependent peroxidase 4 (GPX4) was inactivated via GSH depletion following I/R injury, whereas GPX4 activation blocked I/R‑induced ferroptosis by reducing lipid ROS levels. The mitogen‑activated protein kinase (MAPK) pathway was also investigated in the present study; it was observed that I/R‑induced ferroptosis was blocked by inhibiting p38 MAPK activation. The results of the present study demonstrate that ferroptosis is a pervasive and dynamic type of cell death induced by OGD/R injury in Sertoli cells. This may provide a novel insight into the application of cytoprotection in testicular I/R damage‑induced cell loss.

USP22 Protects Against Myocardial Ischemia–Reperfusion Injury via the SIRT1-p53/SLC7A11–Dependent Inhibition of Ferroptosis–Induced Cardiomyocyte Death

“…Consistently, the up-regulation of USP22 has been proven to promote intestinal cell proliferation and tissue regeneration following I/R or hypoxia/reoxygenation, thus exerting a similar protective function on intestinal I/R injury (Ji et al, 2019). Ferroptosis is involved in the oxygen-glucose deprivation/reoxygenation-induced Sertoli cell death, commonly characterized by elevated iron and lipid reactive oxygen species levels in I/R injury and depleted GSH (Li et al, 2018).…”

Cigarette smoking is associated with high level of ferroptosis in seminal plasma and affects semen quality

“…Ferroptosis, a new regulated cell death identified by Brent R. Stockwell's lab in 2012, is mediated by an iron dependent accumulation of lipid reactive oxygen species (ROS) . Study by Li et al showed that ferroptosis is a pervasive and dynamic type of cell death induced by Oxygen-glucose deprivation and reoxygenation injury in Sertoli cells [28], Elizabeth G explored the contribution of ferroptosis to the demise of germline cells during periods of acute stress in vivo [29]. Previous studies have verified that the lethal lipid peroxidation reaction is accelerated by intracellular iron in the germ cells, whereas other divalent cationic metals have no effect [38,39].…”

Iron Metabolism in Ferroptosis

“…The knockdown of SLC40A1 by RNAi or HAMP-mediated downregulation of SLC40A1 promotes erastin-induced ferroptosis, while ponasterone (a SLC40A1 inducer) impedes this process (Geng et al, 2018). Similarly, the knockdown of SLC40A1 enhances oxygen-glucose deprivation and reoxygenation (OGd/R)-induced ferroptosis in testicular ischemia-reperfusion (I/R) injury sertoli cells (Li L. et al, 2018). In contrast, the overexpression of SLC40A1 or treatment with ponasterone rescues OGd/R-induced ferroptosis by decreasing iron accumulation in sertoli cells (Li L. et al, 2018).…”