Institute of Experimental Diabetes Research, Hannover Medical School, 30625, Hannover, Germany; Institute of Clinical Biochemistry, Hannover Medical School, 30625, Hannover, Germany.
Institute of Clinical Biochemistry, Hannover Medical School, 30625, Hannover, Germany.
Biochim Biophys Acta Mol Basis Dis. 2021 Jun 1;1867(6):166114. doi: 10.1016/j.bbadis.2021.166114. Epub 2021 Mar 2.
Pro-inflammatory cytokines are crucial mediators of beta-cell destruction in type 1 diabetes mellitus (T1DM). The involvement of ferroptosis as a form of oxidative non-apoptotic cell death in T1DM pathogenesis has not been elucidated so far. Moreover, the role of glutathione peroxidase 4 (GPx4) as an antioxidative enzyme and a major regulator of ferroptosis remains elusive. Assessment of GPx4 expression in different pancreatic islet cell types revealed a predominant expression in beta-cells. Silencing of GPx4 by RNA interference and exposure to tert-butyl hydroperoxide (tert-BHP) caused ferroptosis in rat pancreatic beta-cells as evidenced by non-apoptotic cell death in association with increased lipid peroxidation, disturbed ATP synthesis, reduced GSH content, and GPx4 degradation. GPx4 overexpression as well as the ferroptosis inhibitor ferrostatin-1 effectively attenuated beta-cell death induced by tert-BHP. Notably, beta-cell toxic cytokines did not induce ferroptosis although beta-cells underwent cell death. Inhibition of iNOS by Nω-nitro-L-arginine however led to a massive lipid peroxidation upon exposure to pro-inflammatory cytokines. Hence, nitric oxide produced during pro-inflammatory cytokine action prevents the induction of ferroptosis, thereby favouring apoptosis as a primary cell death mechanism. The extraordinarily high abundance of the phospholipid hydroperoxidase GPx4 in beta-cells in contrast to the very low expression in other islet cell types points to a susceptibility of beta-cells to the accumulation of toxic lipid peroxides. Overall, these data strongly suggest that GPx4 is indispensable for beta-cell function under physiological conditions. On the other hand, our results exclude an involvement of ferroptosis as an alternative beta-cell death mode under pro-inflammatory cytokine attack.
促炎细胞因子是 1 型糖尿病（T1DM）中β细胞破坏的关键介质。铁死亡作为 T1DM 发病机制中一种氧化非凋亡性细胞死亡形式的参与尚未阐明。此外，谷胱甘肽过氧化物酶 4（GPx4）作为抗氧化酶和铁死亡的主要调节剂的作用仍然难以捉摸。评估不同胰岛细胞类型中 GPx4 的表达情况表明，β细胞中存在主要表达。用 RNA 干扰沉默 GPx4 并用叔丁基过氧化氢（tert-BHP）处理会导致大鼠胰腺β细胞发生铁死亡，这与非凋亡性细胞死亡有关，同时伴随着脂质过氧化增加、ATP 合成紊乱、GSH 含量减少和 GPx4 降解。GPx4 过表达和铁死亡抑制剂 ferrostatin-1 可有效减轻 tert-BHP 诱导的β细胞死亡。值得注意的是，β细胞毒性细胞因子虽然会导致β细胞死亡，但不会诱导铁死亡。然而，抑制 iNOS 会导致在暴露于促炎细胞因子时发生大量脂质过氧化。因此，促炎细胞因子作用过程中产生的一氧化氮会阻止铁死亡的诱导，从而促进细胞凋亡作为主要的细胞死亡机制。β细胞中磷脂氢过氧化物酶 GPx4 的丰度极高，而其他胰岛细胞类型中的表达非常低，这表明β细胞容易积聚有毒的脂质过氧化物。总的来说，这些数据强烈表明 GPx4 在生理条件下对β细胞功能是必不可少的。另一方面，我们的结果排除了铁死亡作为促炎细胞因子攻击下替代的β细胞死亡模式的参与。
