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Dysregulation of hydrogen sulfide (H<jats:sub>2<\/jats:sub>S) by inhibition of cystathionine \u03b3-lyase (CSE) increases sFlt-1 and soluble endoglin (sEng) release. We explored whether compromise in CSE\/H<jats:sub>2<\/jats:sub>S pathway is linked to dysregulation of the mitochondrial bioenergetics and oxidative status. We investigated whether these effects were linked to CSE-induced sFlt-1 and sEng production in endothelial cells. Here, we demonstrate that CSE\/H<jats:sub>2<\/jats:sub>S pathway sustain endothelial mitochondrial bioenergetics and loss of CSE increases the production of mitochondrial-specific superoxide. As a compensatory effect, low CSE environment enhances the reliance on glycolysis. The mitochondrial-targeted H<jats:sub>2<\/jats:sub>S donor, AP39, suppressed the antiangiogenic response and restored the mitochondrial bioenergetics in endothelial cells. AP39 revealed that upregulation of sFlt-1, but not sEng, is independent of the mitochondrial H<jats:sub>2<\/jats:sub>S metabolising enzyme, SQR. These data provide new insights into the molecular mechanisms for antiangiogenic upregulation in a mitochondrial-driven environment. Targeting H<jats:sub>2<\/jats:sub>S to the mitochondria may be of therapeutic benefit in the prevention of endothelial dysfunction associated with preeclampsia.<\/jats:p>","DOI":"10.1038\/s41598-020-72371-2","type":"journal-article","created":{"date-parts":[[2020,9,25]],"date-time":"2020-09-25T10:02:43Z","timestamp":1601028163000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Bioenergetic effects of hydrogen sulfide suppress soluble Flt-1 and soluble endoglin in cystathionine gamma-lyase compromised endothelial cells"],"prefix":"10.1038","volume":"10","author":[{"given":"Lissette Carolina","family":"Sanchez-Aranguren","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shakil","family":"Ahmad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irundika H. 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