Hydrogen sulfide guards myoblasts from ferroptosis by inhibiting ALOX12 acetylation
Hydrogen sulfide guards myoblasts from ferroptosis by inhibiting ALOX12 acetylation
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DOI：
10.1016/j.cellsig.2020.109870
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发表时间：
2021-02-01
影响因子：
4.8
通讯作者：
Yang, Guangdong
中科院分区：
文献类型：
--
作者：
Wang, Yuehong;Yu, Ruihuan;Yang, Guangdong
硫化氢（H2S）是一种新型的重要气体传递物质，广泛存在于各种组织和器官中。胱氨酸γ -裂解酶（CSE）衍生的H2S已被证明可以调节氧化应激和脂质代谢。本研究的目的是研究H2S在小鼠成肌细胞和骨骼肌的铁下垂和脂质过氧化中的作用。铁沉激动剂RSL3抑制Gpx4的表达，降低CSE/H2S信号，导致氧化应激、脂质过氧化和铁沉细胞死亡增加。此外，铁凋亡拮抗剂铁抑素-1 （fer1）上调CSE的表达，清除活性氧（ROS）的产生和脂质过氧化，提高细胞活力。外源性应用NaHS也能阻断rsl3诱导的铁致细胞死亡。RSL3和H2S均不影响细胞凋亡。此外，H2S逆转rsl3诱导的Drp1表达和线粒体损伤，导致脂质代谢异常，表现为细胞质和线粒体中ACSL4、FAS、ACC和CPT1的表达改变以及乙酰辅酶a含量升高。RSL3促进了启动膜磷脂氧化的关键蛋白ALOX12的蛋白表达和乙酰化，而NaHS的加入减弱了ALOX12的乙酰化，保护了膜脂过氧化。此外，我们观察到CSE缺乏改变了衰老或损伤条件下小鼠骨骼肌中铁下沉和脂质过氧化相关蛋白的表达，并增强了整体蛋白乙酰化。这些结果表明，CSE/H2S信号的下调会导致线粒体损伤、脂质代谢异常、膜脂过氧化和铁致细胞死亡。CSE/H2S系统可作为预防骨骼肌铁下垂的靶点。
Recognized as a novel and important gasotransmitter, hydrogen sulfide (H2S) is widely present in various tissues and organs. Cystathionine gamma-lyase (CSE)-derived H2S has been shown to regulate oxidative stress and lipid metabolism. The aim of the present study is to examine the role of H2S in ferroptosis and lipid peroxidation in mouse myoblasts and skeletal muscles. Ferroptosis agonist RSL3 inhibited the expressions of Gpx4 and reduced CSE/H2S signaling, which lead to increased oxidative stress, lipid peroxidation, and ferroptotic cell death. In addition, ferroptosis antagonist ferrostatin-1 (Fer-1) up-regulated the expression of CSE, scavenged the generation of reactive oxygen species (ROS) and lipid peroxidation, and improved cell viability. Exogenously applied NaHS was also able to block RSL3-induced ferroptotic cell death. Neither RSL3 nor H2S affected cell apoptosis. Furthermore, H2S reversed RSL3-induced Drp1 expression and mitochondrial damage, which lead to abnormal lipid metabolism as evidenced by altered expressions of ACSL4, FAS, ACC and CPT1 as well as higher acetyl-CoA contents in both cytoplasm and mitochondria. RSL3 promoted the protein expression and acetylation of ALOX12, a key protein in initiating membrane phospholipid oxidation, while the addition of NaHS attenuated ALOX12 acetylation and protected from membrane lipid peroxidation. Moreover, we observed that CSE deficiency alters the expressions of ferroptosis and lipid peroxidation-related proteins and enhances global protein acetylation in mouse skeletal muscles under aging or injury conditions. These results indicate that downregulation of CSE/H2S signaling would contribute to mitochondrial damage, abnormal lipid metabolism, membrane lipid peroxidation, and ferroptotic cell death. CSE/H2S system can be a target for preventing ferroptosis in skeletal muscle.