Thiosulphate sulfurtransferase: Biological roles and therapeutic potential

Abstract

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 (H₂S) metabolism by catalyzing the transfer of sulfur from persulfides (R-SSH) to thiosulfate (S₂O₃^2-), promoting H₂S 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.

Keywords: Mitochondrial dysfunction; Oxidative stress; Redox signaling; Thiosulfate sulfurtransferase (TST).

Graphical abstract

Fig. 1

A conceptual framework of biological effects of TST in mammalian cells. 1. Sulfur metabolism: Sulfur is essential for redox signaling, H2S formation and antioxidant defense. TST plays a role in H2S metabolism, working with enzymes such as MPST. TST interacts with the thiol-dependent antioxidant system GSH and TXN systems, essential for cellular antioxidant defense. TST deficiency causes oxidative stress by disrupting redox balance, increasing ROS and lowering GSH levels. Additionally, TST supports the function of iron-sulfur (Fe–S) clusters, essential for mitochondrial processes like the electron transport chain (ETC). It helps to protect and restore Fe–S enzymes under oxidative stress conditions. 2. Oxygen metabolism: oxygen supports ATP production but also generates ROS, potentially damaging cells. TST interacts to regulate ROS level, maintaining redox balance. Studies indicate TST's antioxidative role extends to reducing mitochondrial ROS under conditions of oxidative stress. 3. Selenium metabolism: Selenium is crucial for the function of selenoproteins like GPX4 and TXN, which are essential for detoxifying excessive ROS. TSTD1 has been reported to be able to donate sulfane sulfur from S2O32− to TRX, and alternatively TRX could potentially function as a persulfide donor. 4. Reactive Species Interactome (RSI): The RSI integrates multiple reactive species, including ROS, RNS, RSS, and RCS, with enzymatic cellular antioxidant and redox pathways and mitochondrial activity. TST plays a significant role in maintaining redox balance. 5. Extra-mitochondrial TST functions and NRF2 signaling: TST impacts antioxidant responses by possible interaction with KEAP1 protein mediated by H2S, further influencing NRF2, a key regulator of genes that manage oxidative stress. NRF2 activation enhances antioxidant defenses, linking TST's roles both within and beyond mitochondria. Abbreviations are listed in Table 1.

Fig. 2

Clinical relevance of TST expression profiles and disease associations.

Fig. 3

A: Chemical structure of Hit 2, which contains two stereo-centers (indicated by 2 asterisks). B: While the identity of the first stereo center (left∗) can be thereby be determined, assignment of the second stereocenter (right∗) cannot be made from the data from the chiral column alone.