Luo Yang, Melhem Shaden, Feelisch Martin, Chatre Laurent, Morton Nicholas M, Dolga Amalia M, van Goor Harry
University of Groningen, Dept. of Molecular Pharmacology, Groningen Research Institute of Pharmacy, Faculty of Science and Engineering, Groningen, the Netherlands; University Medical Center Groningen, Dept. of Pathology and Medical Biology, Groningen, the Netherlands.
Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Redox Biol. 2025 May;82:103595. doi: 10.1016/j.redox.2025.103595. Epub 2025 Mar 14.
Mitochondria are central to eukaryotic cell function, driving energy production, intermediary metabolism, and cellular homeostasis. Dysregulation of mitochondrial function often results in oxidative stress, a hallmark of numerous diseases, underscoring the critical need for maintaining mitochondrial integrity. Among mitochondrial enzymes, thiosulfate sulfurtransferase (TST) has emerged as a key regulator of sulfur metabolism, redox balance, and Fe-S protein maintenance. Beyond its well-known role in cyanide detoxification, TST facilitates hydrogen sulfide (HS) metabolism by catalyzing the transfer of sulfur from persulfides (R-SSH) to thiosulfate (SO), promoting HS oxidation and preventing its toxic accumulation. Additionally, TST contributes to the thiol-dependent antioxidant system by regulating reactive sulfur species and sustaining mitochondrial functionality through its role in sulfide-driven bioenergetics. This review highlights the biochemical and therapeutic significance of TST in mitochondrial and cellular health, emphasizing its protective roles in diseases associated with oxidative stress and mitochondrial dysfunction. Dysregulation of TST has been implicated in diverse pathologies, including specific metabolic disorders, neurological diseases, cardiovascular conditions, kidney dysfunction, inflammatory bowel disease, and cancer. These associations underline TST's potential as a biomarker and therapeutic target. Therapeutic strategies to activate the TST pathway are explored, with a focus on sodium thiosulfate (STS), novel small molecule (Hit 2), and recombinant hTST protein. STS, an FDA-approved compound, has demonstrated antioxidant and anti-inflammatory effects across multiple preclinical models, mitigating oxidative damage and improving mitochondrial integrity. A slow-release oral formulation of STS is under development, offering promise for expanding its clinical applications. Small molecule activators like Hit 2 and hTST protein have shown efficacy in enhancing mitochondrial respiration and reducing oxidative stress, though both reagents need further in vitro and in vivo investigations. Despite promising advancements, TST-based therapies remain underexplored. Future research should focus on leveraging TST's interplay with pathways like NRF2 signaling, investigating its broader protective roles in cellular health, and developing targeted interventions. Enhancing TST activity represents an innovative therapeutic approach for addressing mitochondrial dysfunction, oxidative stress, and their associated pathologies, offering new hope for the treatment of diseases associated with mitochondrial dysfunction.
线粒体对于真核细胞功能至关重要，驱动能量产生、中间代谢和细胞内稳态。线粒体功能失调常导致氧化应激，这是众多疾病的一个标志，凸显了维持线粒体完整性的迫切需求。在线粒体酶中，硫代硫酸盐硫转移酶（TST）已成为硫代谢、氧化还原平衡和铁硫蛋白维持的关键调节因子。除了其在氰化物解毒中众所周知的作用外，TST通过催化硫从过硫化物（R-SSH）转移到硫代硫酸盐（SO）来促进硫化氢（HS）代谢，促进HS氧化并防止其毒性积累。此外，TST通过调节活性硫物种并通过其在硫化物驱动的生物能量学中的作用维持线粒体功能，从而有助于硫醇依赖性抗氧化系统。本综述强调了TST在线粒体和细胞健康中的生化和治疗意义，强调了其在与氧化应激和线粒体功能障碍相关疾病中的保护作用。TST失调与多种病理状况有关，包括特定的代谢紊乱、神经疾病、心血管疾病、肾功能障碍、炎症性肠病和癌症。这些关联突显了TST作为生物标志物和治疗靶点的潜力。本文探讨了激活TST途径的治疗策略，重点关注硫代硫酸钠（STS）、新型小分子（Hit 2）和重组人TST蛋白。STS是一种经美国食品药品监督管理局批准的化合物，已在多个临床前模型中显示出抗氧化和抗炎作用，减轻氧化损伤并改善线粒体完整性。一种缓释口服制剂正在研发中，有望扩大其临床应用。像Hit 2这样的小分子激活剂和hTST蛋白已显示出增强线粒体呼吸和降低氧化应激的功效，不过这两种试剂都需要进一步的体外和体内研究。尽管取得了有前景的进展，但基于TST的疗法仍未得到充分探索。未来的研究应侧重于利用TST与NRF2信号通路等途径的相互作用，研究其在细胞健康中的更广泛保护作用，并开发针对性干预措施。增强TST活性代表了一种创新的治疗方法，用于解决线粒体功能障碍、氧化应激及其相关病理状况，为治疗与线粒体功能障碍相关的疾病带来了新希望。
