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At the core of this issue lies mitochondrial dysfunction. Hence, strategies that prime mitochondria towards damage resilience might prove applicable in a clinical setting. A promising approach has been to induce a mitohormetic response, removing less capable organelles, and replacing them with more competent ones, in preparation for an insult. Recently, a soluble form of adenylyl cyclase (sAC) has been shown to exist within mitochondria, the activation of which improved mitochondrial function. Here, we sought to understand if inhibiting mitochondrial sAC would elicit mitohormesis and protect the liver from I\/R injury. Wistar male rats were pretreated with LRE1, a specific sAC inhibitor, prior to the induction of hepatic I\/R injury, after which mitochondria were collected and their metabolic function was assessed. We find LRE1 to be an effective inducer of a mitohormetic response based on all parameters tested, a phenomenon that appears to require the activity of the NAD+-dependent sirtuin deacylase (SirT3) and the subsequent deacetylation of mitochondrial proteins. We conclude that LRE1 pretreatment leads to a mitohormetic response that protects mitochondrial function during I\/R injury.<\/jats:p>","DOI":"10.3390\/ijms21144896","type":"journal-article","created":{"date-parts":[[2020,7,14]],"date-time":"2020-07-14T09:30:49Z","timestamp":1594719049000},"page":"4896","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Soluble Adenylyl Cyclase Inhibitor LRE1 Prevents Hepatic Ischemia\/Reperfusion Damage Through Improvement of Mitochondrial Function"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1244-275X","authenticated-orcid":false,"given":"Jo\u00e3o S.","family":"Teodoro","sequence":"first","affiliation":[{"name":"Center for Neurosciences and Cell Biology of the University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Department of Life Sciences of the University of Coimbra, 3000-456 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7720-6264","authenticated-orcid":false,"given":"Jo\u00e3o A.","family":"Amorim","sequence":"additional","affiliation":[{"name":"Center for Neurosciences and Cell Biology of the University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"IIIUC\u2014Institute of Interdisciplinary Research of the University of Coimbra, 3030-789 Coimbra, Portugal"},{"name":"Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9666-4594","authenticated-orcid":false,"given":"Ivo F.","family":"Machado","sequence":"additional","affiliation":[{"name":"Center for Neurosciences and Cell Biology of the University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Department of Life Sciences of the University of Coimbra, 3000-456 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana C.","family":"Castela","sequence":"additional","affiliation":[{"name":"Center for Neurosciences and Cell Biology of the University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Department of Life Sciences of the University of Coimbra, 3000-456 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens","family":"Steegborn","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Sinclair","sequence":"additional","affiliation":[{"name":"Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Laboratory for Ageing Research, Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anabela P.","family":"Rolo","sequence":"additional","affiliation":[{"name":"Center for Neurosciences and Cell Biology of the University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Department of Life Sciences of the University of Coimbra, 3000-456 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos M.","family":"Palmeira","sequence":"additional","affiliation":[{"name":"Center for Neurosciences and Cell Biology of the University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Department of Life Sciences of the University of Coimbra, 3000-456 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,11]]},"reference":[{"key":"ref_1","first-page":"184","article-title":"Addition of Berberine to Preservation Solution in an Animal Model of Ex Vivo Liver Transplant Preserves Mitochondrial Function and Bioenergetics from the Damage Induced by Ischemia\/Reperfusion","volume":"19","author":"Martins","year":"2011","journal-title":"Int. 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