Thiosulfate sulfurtransferase deficiency promotes oxidative distress and aberrant NRF2 function in the brain
Thiosulfate sulfurtransferase (TST, EC 2.8.1.1) was discovered as an enzyme that detoxifies cyanide by conversion to thiocyanate (rhodanide) using thiosulfate as substrate; this rhodanese activity was subsequently identified to be almost exclusively located in mitochondria. More recently, the emphas...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-12-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221323172300366X |
| _version_ | 1797405435209187328 |
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| author | Yang Luo Laurent Chatre Shaden Melhem Zayana M. Al-Dahmani Natalie Z.M. Homer Anneke Miedema Leo E. Deelman Matthew R. Groves Martin Feelisch Nicholas M. Morton Amalia Dolga Harry van Goor |
| author_facet | Yang Luo Laurent Chatre Shaden Melhem Zayana M. Al-Dahmani Natalie Z.M. Homer Anneke Miedema Leo E. Deelman Matthew R. Groves Martin Feelisch Nicholas M. Morton Amalia Dolga Harry van Goor |
| author_sort | Yang Luo |
| collection | DOAJ |
| description | Thiosulfate sulfurtransferase (TST, EC 2.8.1.1) was discovered as an enzyme that detoxifies cyanide by conversion to thiocyanate (rhodanide) using thiosulfate as substrate; this rhodanese activity was subsequently identified to be almost exclusively located in mitochondria. More recently, the emphasis regarding its function has shifted to hydrogen sulfide metabolism, antioxidant defense, and mitochondrial function in the context of protective biological processes against oxidative distress. While TST has been described to play an important role in liver and colon, its function in the brain remains obscure. In the present study, we therefore sought to address its potential involvement in maintaining cerebral redox balance in a murine model of global TST deficiency (Tst−/− mice), primarily focusing on characterizing the biochemical phenotype of TST loss in relation to neuronal activity and sensitivity to oxidative stress under basal conditions. Here, we show that TST deficiency is associated with a perturbation of the reactive species interactome in the brain cortex secondary to altered ROS and RSS (specifically, polysulfide) generation as well as mitochondrial OXPHOS remodeling. These changes were accompanied by aberrant Nrf2-Keap1 expression and thiol-dependent antioxidant function. Upon challenging mice with the redox-active herbicide paraquat (25 mg/kg i.p. for 24 h), Tst−/− mice displayed a lower antioxidant capacity compared to wildtype controls (C57BL/6J mice). These results provide a first glimpse into the molecular and metabolic changes of TST deficiency in the brain and suggest that pathophysiological conditions associated with aberrant TST expression and/or activity renders neurons more susceptible to oxidative stress-related malfunction. |
| first_indexed | 2024-03-09T03:10:55Z |
| format | Article |
| id | doaj.art-60a049bd7a644081bdd281cc51e743d3 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-03-09T03:10:55Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-60a049bd7a644081bdd281cc51e743d32023-12-04T05:21:51ZengElsevierRedox Biology2213-23172023-12-0168102965Thiosulfate sulfurtransferase deficiency promotes oxidative distress and aberrant NRF2 function in the brainYang Luo0Laurent Chatre1Shaden Melhem2Zayana M. Al-Dahmani3Natalie Z.M. Homer4Anneke Miedema5Leo E. Deelman6Matthew R. Groves7Martin Feelisch8Nicholas M. Morton9Amalia Dolga10Harry van Goor11University of Groningen, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, Faculty of Science and Engineering, Groningen, the Netherlands; University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the NetherlandsUniversité de Caen Normandie, CNRS, Normandie University, ISTCT UMR6030, GIP Cyceron, F-14000 Caen, FranceCentre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United KingdomUniversity of Groningen, Department of Pharmacy, Drug Design, Groningen, the NetherlandsMass Spectrometry Core, Edinburgh Clinical Research Facility, University of Edinburgh/BHF Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburghh, United KingdomUniversity Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the NetherlandsUniversity of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, the NetherlandsUniversity of Groningen, Department of Pharmacy, Drug Design, Groningen, the NetherlandsClinical and Experimental Sciences, Faculty of Medicine, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, United KingdomCentre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom; Centre for Systems Health and Integrated Metabolic Research, School of Science and Technology, Nottingham Trent University, Nottingham, United KingdomUniversity of Groningen, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, Faculty of Science and Engineering, Groningen, the NetherlandsUniversity Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands; Corresponding author.Thiosulfate sulfurtransferase (TST, EC 2.8.1.1) was discovered as an enzyme that detoxifies cyanide by conversion to thiocyanate (rhodanide) using thiosulfate as substrate; this rhodanese activity was subsequently identified to be almost exclusively located in mitochondria. More recently, the emphasis regarding its function has shifted to hydrogen sulfide metabolism, antioxidant defense, and mitochondrial function in the context of protective biological processes against oxidative distress. While TST has been described to play an important role in liver and colon, its function in the brain remains obscure. In the present study, we therefore sought to address its potential involvement in maintaining cerebral redox balance in a murine model of global TST deficiency (Tst−/− mice), primarily focusing on characterizing the biochemical phenotype of TST loss in relation to neuronal activity and sensitivity to oxidative stress under basal conditions. Here, we show that TST deficiency is associated with a perturbation of the reactive species interactome in the brain cortex secondary to altered ROS and RSS (specifically, polysulfide) generation as well as mitochondrial OXPHOS remodeling. These changes were accompanied by aberrant Nrf2-Keap1 expression and thiol-dependent antioxidant function. Upon challenging mice with the redox-active herbicide paraquat (25 mg/kg i.p. for 24 h), Tst−/− mice displayed a lower antioxidant capacity compared to wildtype controls (C57BL/6J mice). These results provide a first glimpse into the molecular and metabolic changes of TST deficiency in the brain and suggest that pathophysiological conditions associated with aberrant TST expression and/or activity renders neurons more susceptible to oxidative stress-related malfunction.http://www.sciencedirect.com/science/article/pii/S221323172300366XThiosulfate sulfurtransferase (TST)Reactive speciesAntioxidantOxidative distressNrf2 signaling |
| spellingShingle | Yang Luo Laurent Chatre Shaden Melhem Zayana M. Al-Dahmani Natalie Z.M. Homer Anneke Miedema Leo E. Deelman Matthew R. Groves Martin Feelisch Nicholas M. Morton Amalia Dolga Harry van Goor Thiosulfate sulfurtransferase deficiency promotes oxidative distress and aberrant NRF2 function in the brain Redox Biology Thiosulfate sulfurtransferase (TST) Reactive species Antioxidant Oxidative distress Nrf2 signaling |
| title | Thiosulfate sulfurtransferase deficiency promotes oxidative distress and aberrant NRF2 function in the brain |
| title_full | Thiosulfate sulfurtransferase deficiency promotes oxidative distress and aberrant NRF2 function in the brain |
| title_fullStr | Thiosulfate sulfurtransferase deficiency promotes oxidative distress and aberrant NRF2 function in the brain |
| title_full_unstemmed | Thiosulfate sulfurtransferase deficiency promotes oxidative distress and aberrant NRF2 function in the brain |
| title_short | Thiosulfate sulfurtransferase deficiency promotes oxidative distress and aberrant NRF2 function in the brain |
| title_sort | thiosulfate sulfurtransferase deficiency promotes oxidative distress and aberrant nrf2 function in the brain |
| topic | Thiosulfate sulfurtransferase (TST) Reactive species Antioxidant Oxidative distress Nrf2 signaling |
| url | http://www.sciencedirect.com/science/article/pii/S221323172300366X |
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