{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:43:46Z","timestamp":1785437026008,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,7]]},"group-title":"Biochemistry","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["23K20040"],"award-info":[{"award-number":["23K20040"]}],"id":[{"id":"https:\/\/ror.org\/00hhkn466","id-type":"ROR","asserted-by":"publisher"}]},{"award":["24H00063"],"award-info":[{"award-number":["24H00063"]}],"id":[{"id":"https:\/\/ror.org\/00hhkn466","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"crossref","award":["JP21zf0127001"],"award-info":[{"award-number":["JP21zf0127001"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Sulfide:quinone oxidoreductase (SQR) is a critical enzyme that maintains sulfur metabolism by oxidizing sulfide to supersulfides, currently defined as sulfur metabolites with six valence electrons and no charge that are covalently catenated with other sulfur atoms and excludes disulfides. While SQR is known to contribute to mitochondrial electron transport, its physiological impact on systemic energy metabolism and longevity remains largely undefined. In this study, we investigated the role of SQR in mitochondrial bioenergetics and aging using SQR-deficient\n                  <jats:italic>Schizosaccharomyces pombe<\/jats:italic>\n                  (\n                  <jats:italic>\u0394hmt2<\/jats:italic>\n                  ) and a mitochondria-selective SQR-deficient (\n                  <jats:italic>Sqrdl<\/jats:italic>\n                  <jats:sup>\u0394N\/\u0394N<\/jats:sup>\n                  ) mice model. Functional analysis demonstrated that\n                  <jats:italic>\u0394hmt2<\/jats:italic>\n                  grew normally in glucose but not in glycerol, indicating impaired mitochondrial respiration. It showed reduced membrane potential, ATP, and lifespan. Consistent with the yeast findings,\n                  <jats:italic>Sqrdl<\/jats:italic>\n                  <jats:sup>\u0394N\/\u0394N<\/jats:sup>\n                  mice exhibited accumulated levels of hydrogen sulfide and persulfides, and demonstrated impaired mitochondrial energy metabolism. Furthermore, supersulfide donor supplementation selectively conferred lifespan extension in wild-type yeast, but not in SQR-deficient strain, and similarly improved mitochondrial function exclusively in wild-type mouse embryonic fibroblasts, with no benefit observed in SQR-mutant counterparts. Together, our findings demonstrate that mitochondrial SQR plays an essential role in sulfur respiration, critically supporting mitochondrial function and organismal longevity across eukaryotes.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphic Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"716515v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>\n                        Developed an SQR-deficient\n                        <jats:italic>S. pombe<\/jats:italic>\n                        (\n                        <jats:italic>\u0394hmt2<\/jats:italic>\n                        ) model that exhibits sulfur metabolism, mitochondrial dysfunction, and shortened chronological lifespan\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Sulfide and supersulfide donors prolong yeast lifespan in a SQR-dependent manner<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Mitochondrial SQR is essential for membrane potential formation and ATP production in yeast and mammals<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.05.716515","type":"posted-content","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T01:10:34Z","timestamp":1775610634000},"source":"Crossref","is-referenced-by-count":0,"title":["Sulfide:quinone oxidoreductase drives mitochondrial supersulfide metabolism to regulate bioenergetics and longevity in eukaryotes"],"prefix":"10.64898","author":[{"given":"Jia","family":"Yao","sequence":"first","affiliation":[{"name":"Department of Redox Molecular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuro","family":"Matsunaga","sequence":"additional","affiliation":[{"name":"Department of Redox Molecular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan"},{"name":"Comprehensive Center for Infectious Disease Control, Graduate School of Medicine, Akita University, Akita 010-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Division of Agriculture, Graduate School of Arts and Sciences, Iwate University, Iwate 020-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meg","family":"Shieh","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Brown University, Providence, Rhode Island 02912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoaki","family":"Ida","sequence":"additional","affiliation":[{"name":"Department of Redox Molecular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minkyung","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Redox Molecular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiryo","family":"Ogata","sequence":"additional","affiliation":[{"name":"Department of Environmental Medicine and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan"},{"name":"Max-Planck-Institute for Polymer Research, Mainz 55128, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuyoshi","family":"Takata","sequence":"additional","affiliation":[{"name":"Department of Redox Molecular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uladzimir","family":"Barayeu","sequence":"additional","affiliation":[{"name":"Department of Redox Molecular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan"},{"name":"Max-Planck-Institute for Polymer Research, Mainz 55128, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hozumi","family":"Motohashi","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Graduate School of Medicine Tohoku University, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanobu","family":"Morita","sequence":"additional","affiliation":[{"name":"Department of Environmental Medicine and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaaki","family":"Akaike","sequence":"additional","affiliation":[{"name":"Department of Redox Molecular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026040910002390000_2026.04.05.716515v1.1","doi-asserted-by":"crossref","unstructured":"F. Bouillaud , Sulfide oxidation evidences the immediate cellular response to a decrease in the mitochondrial ATP\/O2 ratio. Biomolecules 12, 361 (2022).","DOI":"10.3390\/biom12030361"},{"key":"2026040910002390000_2026.04.05.716515v1.2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R110.128363"},{"key":"2026040910002390000_2026.04.05.716515v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.101435"},{"key":"2026040910002390000_2026.04.05.716515v1.4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1321232111"},{"key":"2026040910002390000_2026.04.05.716515v1.5","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1089\/ars.2021.0170","article-title":"Chemical biology of reactive sulfur species: hydrolysis-driven equilibrium of polysulfides as a determinant of physiological functions","volume":"36","year":"2022","journal-title":"Antioxid. Redox Signal"},{"key":"2026040910002390000_2026.04.05.716515v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01311-y"},{"key":"2026040910002390000_2026.04.05.716515v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-40182-4"},{"key":"2026040910002390000_2026.04.05.716515v1.8","doi-asserted-by":"crossref","first-page":"eadg8631","DOI":"10.1126\/sciadv.adg8631","article-title":"Supersulfide catalysis for nitric oxide and aldehyde metabolism","volume":"9","year":"2023","journal-title":"Sci. Adv"},{"issue":"1","key":"2026040910002390000_2026.04.05.716515v1.9","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1111\/bph.16271","article-title":"Supersulfide biology and translational medicine for disease control","volume":"183","year":"2026","journal-title":"Br. J. Pharmacol"},{"key":"2026040910002390000_2026.04.05.716515v1.10","doi-asserted-by":"crossref","first-page":"103545","DOI":"10.1016\/j.redox.2025.103545","article-title":"Supersulfides contribute to joint homeostasis and bone regeneration","volume":"81","year":"2025","journal-title":"Redox Biol"},{"key":"2026040910002390000_2026.04.05.716515v1.11","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1111\/cas.16430","article-title":"Supersulfide metabolome of exhaled breath condensate applied as diagnostic biomarkers for esophageal cancer","volume":"116","year":"2025","journal-title":"Cancer Sci"},{"key":"2026040910002390000_2026.04.05.716515v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2024.102440"},{"key":"2026040910002390000_2026.04.05.716515v1.13","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/s41467-024-55661-5","article-title":"Polysulfur-based bulking of dynamin-related protein 1 prevents ischemic sulfide catabolism and heart failure in mice","volume":"16","year":"2025","journal-title":"Nat. Commun"},{"key":"2026040910002390000_2026.04.05.716515v1.14","doi-asserted-by":"crossref","first-page":"102620","DOI":"10.1016\/j.redox.2023.102620","article-title":"Intranasal administration of polysulfide prevents neurodegeneration in spinal cord and rescues mice from delayed paraplegia after spinal cord ischemia","volume":"60","year":"2023","journal-title":"Redox Biol"},{"key":"2026040910002390000_2026.04.05.716515v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2024.07.007"},{"key":"2026040910002390000_2026.04.05.716515v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2010.03.018"},{"key":"2026040910002390000_2026.04.05.716515v1.17","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.19.13250"},{"key":"2026040910002390000_2026.04.05.716515v1.18","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msg174"},{"key":"2026040910002390000_2026.04.05.716515v1.19","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-016-2406-8"},{"key":"2026040910002390000_2026.04.05.716515v1.20","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.602664"},{"key":"2026040910002390000_2026.04.05.716515v1.21","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-014-1983-9"},{"key":"2026040910002390000_2026.04.05.716515v1.22","doi-asserted-by":"crossref","first-page":"103227","DOI":"10.1016\/j.redox.2024.103227","article-title":"Hydrogen sulfide maintains mitochondrial homeostasis and regulates ganoderic acids biosynthesis by SQR under heat stress in Ganoderma lucidum","volume":"74","year":"2024","journal-title":"Redox Biol"},{"key":"2026040910002390000_2026.04.05.716515v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2010.04.004"},{"key":"2026040910002390000_2026.04.05.716515v1.24","first-page":"949","article-title":"Hydrogen sulfide oxidation by sulfide quinone oxidoreductase. Chembiochem Eur","volume":"22","year":"2021","journal-title":"J. Chem. Biol"},{"key":"2026040910002390000_2026.04.05.716515v1.25","doi-asserted-by":"crossref","first-page":"102169","DOI":"10.1016\/j.redox.2021.102169","article-title":"Sulfide-quinone oxidoreductase is required for cysteine synthesis and indispensable to mitochondrial health","volume":"47","year":"2021","journal-title":"Redox Biol"},{"key":"2026040910002390000_2026.04.05.716515v1.26","doi-asserted-by":"crossref","first-page":"116","DOI":"10.3390\/antiox8050116","article-title":"Novel characterization of antioxidant enzyme, 3-mercaptopyruvate sulfurtransferase-knockout mice: overexpression of the evolutionarily-related enzyme rhodanese","volume":"8","year":"2019","journal-title":"Antioxidants"},{"key":"2026040910002390000_2026.04.05.716515v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/nature724"},{"key":"2026040910002390000_2026.04.05.716515v1.28","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.009203"},{"key":"2026040910002390000_2026.04.05.716515v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23363-x"},{"key":"2026040910002390000_2026.04.05.716515v1.30","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14356"},{"key":"2026040910002390000_2026.04.05.716515v1.31","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.788547"},{"key":"2026040910002390000_2026.04.05.716515v1.32","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2011.4186"},{"key":"2026040910002390000_2026.04.05.716515v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/nature02056"},{"issue":"32","key":"2026040910002390000_2026.04.05.716515v1.34","doi-asserted-by":"crossref","first-page":"10898","DOI":"10.1002\/anie.201905580","article-title":"Data-driven identification of hydrogen sulfide scavengers","volume":"58","year":"2019","journal-title":"Angew Chem Int Ed Engl"},{"key":"2026040910002390000_2026.04.05.716515v1.35","doi-asserted-by":"crossref","first-page":"3538","DOI":"10.1046\/j.1432-1327.2001.02257.x","article-title":"In vitro processing of the proproteins GrdE of protein B of glycine reductase and PrdA of D-proline reductase from Clostridium sticklandii","volume":"268","year":"2001","journal-title":"Eur. J. Biochem"},{"key":"2026040910002390000_2026.04.05.716515v1.36","doi-asserted-by":"crossref","first-page":"103018","DOI":"10.1016\/j.redox.2023.103018","article-title":"Longevity control by supersulfide-mediated mitochondrial respiration and regulation of protein quality","volume":"69","year":"2024","journal-title":"Redox Biol"},{"issue":"1","key":"2026040910002390000_2026.04.05.716515v1.37","doi-asserted-by":"crossref","first-page":"2453","DOI":"10.1038\/s41467-024-46652-7","article-title":"2H-Thiopyran-2-thione sulfine, a compound for converting H2S to HSOH\/H2S2 and increasing intracellular sulfane sulfur levels","volume":"15","year":"2024","journal-title":"Nat Commun"},{"key":"2026040910002390000_2026.04.05.716515v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.07.006"},{"key":"2026040910002390000_2026.04.05.716515v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.11.048"},{"key":"2026040910002390000_2026.04.05.716515v1.40","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0710191104"},{"key":"2026040910002390000_2026.04.05.716515v1.41","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1089\/ars.2017.7076","article-title":"Hydrogen sulfide and polysulfide signaling, Antioxid","volume":"27","year":"2017","journal-title":"Redox Signal"},{"key":"2026040910002390000_2026.04.05.716515v1.42","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0061(199807)14:10<953::AID-YEA293>3.0.CO;2-U"},{"key":"2026040910002390000_2026.04.05.716515v1.43","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1002\/(SICI)1097-0061(19990930)15:13<1419::AID-YEA466>3.0.CO;2-Q","article-title":"High-efficiency gene targeting in Schizosaccharomyces pombe using a modular, PCR-based approach with long tracts of flanking homology","volume":"15","year":"1999","journal-title":". Yeast Chichester Engl"},{"key":"2026040910002390000_2026.04.05.716515v1.44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.9.3671"},{"issue":"8","key":"2026040910002390000_2026.04.05.716515v1.45","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.3390\/microorganisms9081650","article-title":"Longevity regulation by proline oxidation in yeast","volume":"9","year":"2021","journal-title":"Microorganisms"},{"key":"2026040910002390000_2026.04.05.716515v1.46","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/S0167-4889(00)00027-6","article-title":"Mitochondrial DNA-depleted neuroblastoma (Rho degrees) cells exhibit altered calcium signaling","volume":"1496","year":"2000","journal-title":"Biochim. Biophys. Acta"},{"key":"2026040910002390000_2026.04.05.716515v1.47","doi-asserted-by":"crossref","unstructured":"G. Nicholls , et al, Bioenergetic profile experiment using C2C12 myoblast cells, J. Vis. Exp. JoVE (2010) 2511.","DOI":"10.3791\/2511"},{"key":"2026040910002390000_2026.04.05.716515v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(99)77214-0"},{"key":"2026040910002390000_2026.04.05.716515v1.49","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.478"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.04.05.716515","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T17:01:03Z","timestamp":1775754063000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.04.05.716515"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,7]]},"references-count":49,"URL":"https:\/\/doi.org\/10.64898\/2026.04.05.716515","relation":{},"subject":[],"published":{"date-parts":[[2026,4,7]]},"subtype":"preprint"}}