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SQR mediates therapeutic effects of H(2)S by targeting mitochondrial electron transport to induce mitochondrial uncoupling
Hydrogen sulfide (H(2)S) is a gasotransmitter and a potential therapeutic agent. However, molecular targets relevant to its therapeutic actions remain enigmatic. Sulfide-quinone oxidoreductase (SQR) irreversibly oxidizes H(2)S. Therefore, SQR is assumed to inhibit H(2)S signaling. We now report that...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449675/ https://www.ncbi.nlm.nih.gov/pubmed/32923620 http://dx.doi.org/10.1126/sciadv.aaz5752 |
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author | Jia, Jia Wang, Zichuang Zhang, Minjie Huang, Caiyun Song, Yanmei Xu, Fuyou Zhang, Jingyu Li, Jie He, Meijun Li, Yuyao Ao, Guizhen Hong, Chengjiao Cao, Yongjun Chin, Y. Eugene Hua, Zi-chun Cheng, Jian |
author_facet | Jia, Jia Wang, Zichuang Zhang, Minjie Huang, Caiyun Song, Yanmei Xu, Fuyou Zhang, Jingyu Li, Jie He, Meijun Li, Yuyao Ao, Guizhen Hong, Chengjiao Cao, Yongjun Chin, Y. Eugene Hua, Zi-chun Cheng, Jian |
author_sort | Jia, Jia |
collection | PubMed |
description | Hydrogen sulfide (H(2)S) is a gasotransmitter and a potential therapeutic agent. However, molecular targets relevant to its therapeutic actions remain enigmatic. Sulfide-quinone oxidoreductase (SQR) irreversibly oxidizes H(2)S. Therefore, SQR is assumed to inhibit H(2)S signaling. We now report that SQR-mediated oxidation of H(2)S drives reverse electron transport (RET) at mitochondrial complex I, which, in turn, repurposes mitochondrial function to superoxide production. Unexpectedly, complex I RET, a process dependent on high mitochondrial membrane potential, induces superoxide-dependent mitochondrial uncoupling and downstream activation of adenosine monophosphate–activated protein kinase (AMPK). SQR-induced mitochondrial uncoupling is separated from the inhibition of mitochondrial complex IV by H(2)S. Moreover, deletion of SQR, complex I, or AMPK abolishes therapeutic effects of H(2)S following intracerebral hemorrhage. To conclude, SQR mediates H(2)S signaling and therapeutic effects by targeting mitochondrial electron transport to induce mitochondrial uncoupling. Moreover, SQR is a previously unrecognized target for developing non-protonophore uncouplers with broad clinical implications. |
format | Online Article Text |
id | pubmed-7449675 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-74496752020-09-11 SQR mediates therapeutic effects of H(2)S by targeting mitochondrial electron transport to induce mitochondrial uncoupling Jia, Jia Wang, Zichuang Zhang, Minjie Huang, Caiyun Song, Yanmei Xu, Fuyou Zhang, Jingyu Li, Jie He, Meijun Li, Yuyao Ao, Guizhen Hong, Chengjiao Cao, Yongjun Chin, Y. Eugene Hua, Zi-chun Cheng, Jian Sci Adv Research Articles Hydrogen sulfide (H(2)S) is a gasotransmitter and a potential therapeutic agent. However, molecular targets relevant to its therapeutic actions remain enigmatic. Sulfide-quinone oxidoreductase (SQR) irreversibly oxidizes H(2)S. Therefore, SQR is assumed to inhibit H(2)S signaling. We now report that SQR-mediated oxidation of H(2)S drives reverse electron transport (RET) at mitochondrial complex I, which, in turn, repurposes mitochondrial function to superoxide production. Unexpectedly, complex I RET, a process dependent on high mitochondrial membrane potential, induces superoxide-dependent mitochondrial uncoupling and downstream activation of adenosine monophosphate–activated protein kinase (AMPK). SQR-induced mitochondrial uncoupling is separated from the inhibition of mitochondrial complex IV by H(2)S. Moreover, deletion of SQR, complex I, or AMPK abolishes therapeutic effects of H(2)S following intracerebral hemorrhage. To conclude, SQR mediates H(2)S signaling and therapeutic effects by targeting mitochondrial electron transport to induce mitochondrial uncoupling. Moreover, SQR is a previously unrecognized target for developing non-protonophore uncouplers with broad clinical implications. American Association for the Advancement of Science 2020-08-26 /pmc/articles/PMC7449675/ /pubmed/32923620 http://dx.doi.org/10.1126/sciadv.aaz5752 Text en Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/ https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Research Articles Jia, Jia Wang, Zichuang Zhang, Minjie Huang, Caiyun Song, Yanmei Xu, Fuyou Zhang, Jingyu Li, Jie He, Meijun Li, Yuyao Ao, Guizhen Hong, Chengjiao Cao, Yongjun Chin, Y. Eugene Hua, Zi-chun Cheng, Jian SQR mediates therapeutic effects of H(2)S by targeting mitochondrial electron transport to induce mitochondrial uncoupling |
title | SQR mediates therapeutic effects of H(2)S by targeting mitochondrial electron transport to induce mitochondrial uncoupling |
title_full | SQR mediates therapeutic effects of H(2)S by targeting mitochondrial electron transport to induce mitochondrial uncoupling |
title_fullStr | SQR mediates therapeutic effects of H(2)S by targeting mitochondrial electron transport to induce mitochondrial uncoupling |
title_full_unstemmed | SQR mediates therapeutic effects of H(2)S by targeting mitochondrial electron transport to induce mitochondrial uncoupling |
title_short | SQR mediates therapeutic effects of H(2)S by targeting mitochondrial electron transport to induce mitochondrial uncoupling |
title_sort | sqr mediates therapeutic effects of h(2)s by targeting mitochondrial electron transport to induce mitochondrial uncoupling |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449675/ https://www.ncbi.nlm.nih.gov/pubmed/32923620 http://dx.doi.org/10.1126/sciadv.aaz5752 |
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