Depolysulfidation of Drp1 induced by low-dose methylmercury exposure increases cardiac vulnerability to hemodynamic overload
Depolysulfidation of Drp1 induced by low-dose methylmercury exposure increases cardiac vulnerability to hemodynamic overload
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DOI：
10.1126/scisignal.aaw1920
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发表时间：
2019-06-25
影响因子：
7.3
通讯作者：
Nishida, Motohiro
中科院分区：
文献类型：
--
作者：
Nishimura, Akiyuki;Shimoda, Kakeru;Nishida, Motohiro
据报道，长期接触环境亲电污染物甲基汞(MeHg)会增加人类心脏事件的风险。我们报道，暴露于低剂量、无神经毒性的甲基汞可导致压力超负荷所致的小鼠心力衰竭。暴露于10ppm的甲基汞不会导致典型的高剂量体重减轻，但会通过鸟核苷酸交换因子丝氨酸A激活Drp1而导致心肌线粒体过度分裂。用西尼地平处理新生大鼠心肌细胞，西尼地平是Drp1和微丝-A相互作用的抑制剂，可抑制低剂量甲基汞暴露引起的线粒体过度分裂。多硫化物修饰蛋白质中的半胱氨酸残基对哺乳动物细胞的氧化还原信号和线粒体动态平衡具有重要意义。我们发现甲基汞以大鼠Drp1为靶向Cys(624)，Cys(624)是一个氧化还原敏感残基，其SH侧链形成一个巨大的亲核多硫化物(Cys(624)-S(N)H)。甲基汞暴露诱导DRP1中Cys(624)-S(N)H解聚，导致DRp1丝胺依赖性激活和线粒体过度分裂。NaHS作为反应性多硫化物的供体，在啮齿动物、人类心肌细胞和小鼠心脏中逆转了由甲基汞引起的DRp1去多硫化和对机械负荷的脆弱性。这些结果表明，低剂量的甲基汞通过丝胺依赖的线粒体超分裂使心肌对机械负荷的脆性增加。
Chronic exposure to methylmercury (MeHg), an environmental electrophilic pollutant, reportedly increases the risk of human cardiac events. We report that exposure to a low, non-neurotoxic dose of MeHg precipitated heart failure induced by pressure overload in mice. Exposure to MeHg at 10 ppm did not induce weight loss typical of higher doses but caused mitochondrial hyperfission in myocardium through the activation of Drp1 by its guanine nucleotide exchange factor filamin-A. Treatment of neonatal rat cardiomyocytes with cilnidipine, an inhibitor of the interaction between Drp1 and filamin-A, suppressed mitochondrial hyperfission caused by low-dose MeHg exposure. Modification of cysteine residues in proteins with polysulfides is important for redox signaling and mitochondrial homeostasis in mammalian cells. We found that MeHg targeted rat Drp1 at Cys(624), a redox-sensitive residue whose SH side chain forms a bulky and nucleophilic polysulfide (Cys(624)-S(n)H). MeHg exposure induced the depolysulfidation of Cys(624)-S(n)H in Drp1, which led to filamin-dependent activation of Drp1 and mitochondrial hyperfission. Treatment with NaHS, which acts as a donor for reactive polysulfides, reversed MeHg-evoked Drp1 depolysulfidation and vulnerability to mechanical load in rodent and human cardiomyocytes and mouse hearts. These results suggest that depolysulfidation of Drp1 at Cys(624)-S(n)H by low-dose MeHg increases cardiac fragility to mechanical load through filamin-dependent mitochondrial hyperfission.