{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T17:19:23Z","timestamp":1784222363710,"version":"3.55.0"},"reference-count":55,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T00:00:00Z","timestamp":1587600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondation J\u00e9r\u00f4me Lejeune","award":["CBS-derived H2S overproduction"],"award-info":[{"award-number":["CBS-derived H2S overproduction"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Down syndrome (trisomy of human chromosome 21) is a common genetic disorder. Overproduction of the gaseous mediator hydrogen sulfide (H2S) has been implicated in the pathogenesis of neurological and metabolic deficits associated with Down syndrome. Several lines of data indicate that an important enzyme responsible for H2S overproduction in Down syndrome is cystathionine-\u03b2-synthase (CBS), an enzyme localized on chromosome 21. The current study explored the possibility that a second H2S-producing enzyme, 3-mercaptopyruvate sulfurtransferase (3-MST), may also contribute to the development of functional deficits of Down syndrome cells. Western blotting analysis demonstrated a significantly higher level of 3-MST protein expression in human Down syndrome fibroblasts compared to cells from healthy control individuals; the excess 3-MST was mainly localized to the mitochondrial compartment. Pharmacological inhibition of 3-MST activity improved mitochondrial electron transport and oxidative phosphorylation parameters (but did not affect the suppressed glycolytic parameters) and enhanced cell proliferation in Down syndrome cells (but not in healthy control cells). The findings presented in the current report suggest that in addition to the indisputable role of CBS, H2S produced from 3-MST may also contribute to the development of mitochondrial metabolic and functional impairments in Down syndrome cells.<\/jats:p>","DOI":"10.3390\/biom10040653","type":"journal-article","created":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T10:46:22Z","timestamp":1587638782000},"page":"653","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Role of 3-Mercaptopyruvate Sulfurtransferase in the Regulation of Proliferation and Cellular Bioenergetics in Human Down Syndrome Fibroblasts"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9399-7107","authenticated-orcid":false,"given":"Theodora","family":"Panagaki","sequence":"first","affiliation":[{"name":"Chair of Pharmacology, Section of Medicine, University of Fribourg, 1700 Fribourg, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa B.","family":"Randi","sequence":"additional","affiliation":[{"name":"Chair of Pharmacology, Section of Medicine, University of Fribourg, 1700 Fribourg, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3110-4235","authenticated-orcid":false,"given":"Csaba","family":"Szabo","sequence":"additional","affiliation":[{"name":"Chair of Pharmacology, Section of Medicine, University of Fribourg, 1700 Fribourg, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.neubiorev.2019.01.001","article-title":"Down syndrome: Neurobiological alterations and therapeutic targets","volume":"98","author":"Vacca","year":"2019","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.neubiorev.2014.01.012","article-title":"Mitochondrial dysfunction as a central actor in intellectual disability-related diseases: An overview of Down syndrome, autism, Fragile X and Rett syndrome","volume":"46","author":"Valenti","year":"2014","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s10020-018-0004-y","article-title":"Mitochondrial dysfunction in Down syndrome: Molecular mechanisms and therapeutic targets","volume":"24","author":"Izzo","year":"2018","journal-title":"Mol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.freeradbiomed.2017.08.014","article-title":"Mitochondria as pharmacological targets in Down syndrome","volume":"114","author":"Valenti","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Szabo, C. (2020). The re-emerging pathophysiological role of the cystathionine-\u03b2-synthase\u2014Hydrogen sulfide system in Down syndrome. FEBS J., in press.","DOI":"10.1111\/febs.15214"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-3-319-18144-8_1","article-title":"H2S synthesizing enzymes: Biochemistry and molecular aspects","volume":"230","author":"Huang","year":"2015","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/978-3-319-18144-8_3","article-title":"Physiological roles of hydrogen sulfide and polysulfides","volume":"230","author":"Kimura","year":"2015","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1124\/pr.117.014050","article-title":"International union of basic and clinical pharmacology. CII: Pharmacological modulation of H2S levels: H2S donors and H2S biosynthesis inhibitors","volume":"69","author":"Szabo","year":"2017","journal-title":"Pharmacol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"18769","DOI":"10.1073\/pnas.1911895116","article-title":"Overproduction of H2S, generated by CBS, inhibits mitochondrial Complex IV and suppresses oxidative phosphorylation in Down syndrome","volume":"116","author":"Panagaki","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.niox.2014.04.008","article-title":"AP39, a novel mitochondria-targeted hydrogen sulfide donor, stimulates cellular bioenergetics, exerts cytoprotective effects and protects against the loss of mitochondrial DNA integrity in oxidatively stressed endothelial cells in vitro","volume":"41","author":"Szczesny","year":"2014","journal-title":"Nitric Oxide"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1021\/ac503806w","article-title":"Toward a selective, sensitive, fast-responsive, and biocompatible two-photon probe for hydrogen sulfide in live cells","volume":"87","author":"Singha","year":"2015","journal-title":"Anal. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"40227","DOI":"10.1038\/srep40227","article-title":"Discovery and mechanistic characterization of selective inhibitors of H2S-producing enzyme: 3-mercaptopyruvate sulfurtransferase (3MST) targeting active-site cysteine persulfide","volume":"7","author":"Hanaoka","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1096\/fj.12-216507","article-title":"Intramitochondrial hydrogen sulfide production by 3-mercaptopyruvate sulfurtransferase maintains mitochondrial electron flow and supports cellular bioenergetics","volume":"27","author":"Coletta","year":"2013","journal-title":"FASEB J."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Augsburger, F., Randi, E.B., Jendly, M., Ascencao, K., Dilek, N., and Szabo, C. (2020). Role of 3-mercaptopyruvate sulfurtransferase in the regulation of proliferation, migration, and bioenergetics in murine colon cancer cells. Biomolecules, 10.","DOI":"10.3390\/biom10030447"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"16158","DOI":"10.1038\/s41598-017-16488-x","article-title":"Liraglutide restores chronic ER stress, autophagy impairments and apoptotic signalling in SH-SY5Y cells","volume":"7","author":"Panagaki","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1054\/mehy.2001.1377","article-title":"Mental retardation in Down syndrome: A hydrogen sulfide hypothesis","volume":"57","author":"Kamoun","year":"2001","journal-title":"Med. Hypotheses"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"109289","DOI":"10.1016\/j.mehy.2019.109289","article-title":"Mental retardation in Down syndrome: Two ways to treat","volume":"131","author":"Kamoun","year":"2019","journal-title":"Med. Hypotheses"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1093\/clinchem\/47.8.1500","article-title":"Urinary sulfur compounds in Down syndrome","volume":"47","author":"Belardinelli","year":"2001","journal-title":"Clin. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1002\/ajmg.a.10847","article-title":"Endogenous hydrogen sulfide overproduction in Down syndrome","volume":"116A","author":"Kamoun","year":"2003","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/0006-291X(85)91641-9","article-title":"Cystathionine beta synthase: Gene dosage effect in trisomy 21","volume":"128","author":"Chadefaux","year":"1985","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_21","first-page":"1393","article-title":"Expression of chromosome 21-localized genes in acute myeloid leukemia: Differences between Down syndrome and non-Down syndrome blast cells and relationship to in vitro sensitivity to cytosine arabinoside and daunorubicin","volume":"94","author":"Taub","year":"1999","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1182\/blood-2002-07-2337","article-title":"Transcriptional regulation of the cystathionine-beta -synthase gene in Down syndrome and non-Down syndrome megakaryocytic leukemia cell lines","volume":"101","author":"Ge","year":"2003","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1016\/j.bbrc.2005.10.118","article-title":"Cystathionine beta-synthase is enriched in the brains of Down\u2019s patients","volume":"338","author":"Ichinohe","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1093\/hmg\/ddy447","article-title":"CBS overdosage is necessary and sufficient to induce cognitive phenotypes in mouse models of Down syndrome and interacts genetically with Dyrk1a","volume":"28","author":"Marechal","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e16220","DOI":"10.7554\/eLife.16220","article-title":"Trisomy 21 consistently activates the interferon response","volume":"5","author":"Sullivan","year":"2016","journal-title":"Elife"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"32353","DOI":"10.1038\/srep32353","article-title":"An integrated human\/murine transcriptome and pathway approach to identify prenatal treatments for Down syndrome","volume":"6","author":"Guedj","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"125","DOI":"10.3389\/fgene.2018.00125","article-title":"Integrated quantitative transcriptome maps of human trisomy 21 tissues and cells","volume":"9","author":"Pelleri","year":"2018","journal-title":"Front. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1016\/j.ijbiomac.2018.09.056","article-title":"Differentially expressed gene (DEG) based protein-protein interaction (PPI) network identifies a spectrum of gene interactome, transcriptome and correlated miRNA in nondisjunction Down syndrome","volume":"122","author":"Sriroopreddy","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7113","DOI":"10.1007\/s12035-019-1585-3","article-title":"Transcriptome and proteome profiling of neural induced pluripotent stem cells from individuals with Down syndrome disclose dynamic dysregulations of key pathways and cellular functions","volume":"56","author":"Sobol","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7497","DOI":"10.18632\/oncotarget.7120","article-title":"Modular transcriptional repertoire and MicroRNA target analyses characterize genomic dysregulation in the thymus of Down syndrome infants","volume":"7","author":"Bando","year":"2016","journal-title":"Oncotarget"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1007\/s10038-008-0279-x","article-title":"Global correlation analysis for micro-RNA and mRNA expression profiles in human cell lines","volume":"53","author":"Ruike","year":"2008","journal-title":"J. Hum. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1590\/1414-431X20143792","article-title":"Bioinformatics analysis of biomarkers and transcriptional factor motifs in Down syndrome","volume":"47","author":"Kong","year":"2014","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.cmet.2012.12.005","article-title":"Adaptive downregulation of mitochondrial function in Down syndrome","volume":"17","author":"Helguera","year":"2013","journal-title":"Cell Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1038\/s41467-017-01422-6","article-title":"Systematic proteome and proteostasis profiling in human Trisomy 21 fibroblast cells","volume":"8","author":"Liu","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1093\/nar\/gkz1128","article-title":"mitoXplorer, a visual data mining platform to systematically analyze and visualize mitochondrial expression dynamics and mutations","volume":"48","author":"Yim","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"104083","DOI":"10.1016\/j.phrs.2018.11.034","article-title":"Potential role of the 3-mercaptopyruvate sulfurtransferase (3-MST)-hydrogen sulfide (H2S) pathway in cancer cells","volume":"154","author":"Augsburger","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.bcp.2017.10.011","article-title":"Role of endogenous and exogenous nitric oxide, carbon monoxide and hydrogen sulfide in HCT116 colon cancer cell proliferation","volume":"149","author":"Hellmich","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_38","first-page":"e00272-18","article-title":"H2S, a bacterial defense mechanism against the host immune response","volume":"87","author":"Cui","year":"2018","journal-title":"Infect. Immun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1111\/bph.14574","article-title":"3-Mercaptopyruvate sulfurtransferase supports endothelial cell angiogenesis and bioenergetics","volume":"177","author":"Szaniszlo","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.cardiores.2007.05.026","article-title":"The novel proangiogenic effect of hydrogen sulfide is dependent on Akt phosphorylation","volume":"76","author":"Cai","year":"2007","journal-title":"Cardiovasc. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1620\/tjem.221.125","article-title":"Hydrogen sulfide, a gaseous transmitter, stimulates proliferation of interstitial cells of Cajal via phosphorylation of AKT protein kinase","volume":"221","author":"Huang","year":"2010","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"21972","DOI":"10.1073\/pnas.0908047106","article-title":"Hydrogen sulfide is an endogenous stimulator of angiogenesis","volume":"106","author":"Papapetropoulos","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"C3","DOI":"10.1152\/ajpcell.00282.2016","article-title":"Hydrogen sulfide, an enhancer of vascular nitric oxide signaling: Mechanisms and implications","volume":"312","author":"Szabo","year":"2017","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4322","DOI":"10.1111\/bph.12773","article-title":"Utilizing hydrogen sulfide as a novel anti-cancer agent by targeting cancer glycolysis and pH imbalance","volume":"171","author":"Lee","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/j.tibs.2015.08.007","article-title":"H2S: A Novel gasotransmitter that signals by sulfhydration","volume":"40","author":"Paul","year":"2015","journal-title":"Trends Biochem. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"111683","DOI":"10.1016\/j.yexcr.2019.111683","article-title":"3-Mercaptopyruvate sulfurtransferase disruption in dermal fibroblasts facilitates adipogenic trans-differentiation","volume":"385","author":"Ostrakhovitch","year":"2019","journal-title":"Exp. Cell Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"608","DOI":"10.3389\/fphar.2017.00608","article-title":"H2S-induced sulfhydration: Biological function and detection methodology","volume":"8","author":"Zhang","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1111\/bph.14100","article-title":"Multiple role of 3-mercaptopyruvate sulfurtransferase: Antioxidative function, H2S and polysulfide production and possible SOx production","volume":"175","author":"Nagahara","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_49","first-page":"71","article-title":"Down syndrome\u2014A gene dosage disease caused by trisomy of genes within a small segment of the long arm of chromosome 21, exemplified by the study of effects from the superoxide-dismutase type 1 (SOD-1) gene","volume":"40","author":"Edman","year":"1993","journal-title":"APMIS Suppl."},{"key":"ref_50","first-page":"535","article-title":"Oxidative stress and Down syndrome. Do antioxidants play a role in therapy?","volume":"63","year":"2014","journal-title":"Physiol. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3958","DOI":"10.1007\/s12035-018-1323-2","article-title":"Alterations in the serotonin and dopamine pathways by cystathionine beta synthase overexpression in murine brain","volume":"56","author":"London","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"R\u00e9gnier, V., Billard, J.M., Gupta, S., Potier, B., Woerner, S., Paly, E., Ledru, A., David, S., Luilier, S., and Bizot, J.C. (2012). Brain phenotype of transgenic mice overexpressing cystathionine \u03b2-synthase. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0029056"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1038\/srep01986","article-title":"Antioxidant enzyme, 3-mercaptopyruvate sulfurtransferase-knockout mice exhibit increased anxiety-like behaviors: A model for human mercaptolactate-cysteine disulfiduria","volume":"3","author":"Nagahara","year":"2013","journal-title":"Sci. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e10695","DOI":"10.15252\/emmm.201910695","article-title":"Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology","volume":"11","author":"Ide","year":"2019","journal-title":"EMBO Mol. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/nm.1907","article-title":"Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy","volume":"15","author":"Tiranti","year":"2009","journal-title":"Nat. Med."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/4\/653\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:45:21Z","timestamp":1760363121000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/4\/653"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,23]]},"references-count":55,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["biom10040653"],"URL":"https:\/\/doi.org\/10.3390\/biom10040653","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,23]]}}}