Kanemaru Eiki, Ichinose Fumito
Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Pharmacol Ther. 2025 Feb;266:108787. doi: 10.1016/j.pharmthera.2024.108787. Epub 2024 Dec 22.
Hydrogen sulfide (HS) is an environmental hazard well known for its neurotoxicity. In mammalian cells, HS is predominantly generated by transsulfuration pathway enzymes. In addition, HS produced by gut microbiome significantly contributes to the total sulfide burden in the body. Although low levels of HS is believed to exert various physiological functions such as neurotransmission and vasomotor control, elevated levels of HS inhibit the activity of cytochrome c oxidase (i.e., mitochondrial complex IV), thereby impairing oxidative phosphorylation. To protect the electron transport chain from respiratory poisoning by HS, the compound is actively oxidized to form persulfides and polysulfides by a mitochondrial resident sulfide oxidation pathway. The reaction, catalyzed by sulfide:quinone oxidoreductase (SQOR), is the initial and critical step in sulfide oxidation. The persulfide species are subsequently oxidized to sulfite, thiosulfate, and sulfate by persulfide dioxygenase (ETHE1 or SDO), thiosulfate sulfurtransferase (TST), and sulfite oxidase (SUOX). While SQOR is abundantly expressed in the colon, liver, lung, and skeletal muscle, its expression is notably low in the brains of most mammals. Consequently, the brain's limited capacity to oxidize HS renders it particularly sensitive to the deleterious effects of HS accumulation. Impaired sulfide oxidation can lead to fatal encephalopathy, and the overproduction of HS has been implicated in the developmental delays observed in Down syndrome. Our recent findings indicate that the brain's limited capacity to oxidize sulfide exacerbates its sensitivity to oxygen deprivation. The beneficial effects of sulfide oxidation are likely to be mediated not only by the detoxification of HS but also by the formation of persulfide, which exerts cytoprotective effects through multiple mechanisms. Therefore, pharmacological agents designed to scavenge HS and/or enhance persulfide levels may offer therapeutic potential against neurological disorders characterized by impaired or insufficient sulfide oxidation or excessive HS production.
硫化氢（HS）是一种以神经毒性而闻名的环境危害物。在哺乳动物细胞中，HS主要由转硫途径酶产生。此外，肠道微生物群产生的HS对体内总硫化物负荷有显著贡献。尽管低水平的HS被认为具有多种生理功能，如神经传递和血管舒缩控制，但HS水平升高会抑制细胞色素c氧化酶（即线粒体复合物IV）的活性，从而损害氧化磷酸化。为保护电子传递链免受HS的呼吸中毒，该化合物通过线粒体驻留的硫化物氧化途径被主动氧化形成过硫化物和多硫化物。由硫化物：醌氧化还原酶（SQOR）催化的该反应是硫化物氧化的初始关键步骤。过硫化物随后被过硫化物双加氧酶（ETHE1或SDO）、硫代硫酸盐硫转移酶（TST）和亚硫酸盐氧化酶（SUOX）氧化为亚硫酸盐、硫代硫酸盐和硫酸盐。虽然SQOR在结肠、肝脏、肺和骨骼肌中大量表达，但其在大多数哺乳动物大脑中的表达明显较低。因此，大脑氧化HS的能力有限使其对HS积累的有害影响特别敏感。硫化物氧化受损可导致致命性脑病，HS的过量产生与唐氏综合征中观察到的发育迟缓有关。我们最近的研究结果表明，大脑氧化硫化物的能力有限会加剧其对缺氧的敏感性。硫化物氧化的有益作用可能不仅通过HS的解毒介导，还通过过硫化物的形成介导，过硫化物通过多种机制发挥细胞保护作用。因此，设计用于清除HS和/或提高过硫化物水平的药物可能对以硫化物氧化受损或不足或HS产生过多为特征的神经系统疾病具有治疗潜力。
