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Although effort has been dedicated to rescuing tissue damage in these clinical settings, there is still an urgent need for an effective treatment to protect the liver from the burden of I\/R injury. In this study, we have investigated the potential clinical impact of unacylated-ghrelin (UnAG) in a liver I\/R rat model. Particular attention has been paid to mitochondria. We demonstrate that UnAG was able to reduce the lag-phase time in response to ADP administration and increase oxygen consumption in<jats:italic>ex vivo<\/jats:italic>experiments using liver mitochondria recovered from rats subjected to I\/R. Moreover, we found that UnAG rescued the expression of a key regulator of mitochondrial morphology and electron transport chain function; the optic atrophy 1 (Opa1) protein. Cytochrome<jats:italic>c<\/jats:italic>oxidase (COX), ATP synthase (complex V) activity and mitochondrial permeability transition pore (mPTP) opening were also affected by UnAG administration<jats:italic>in vivo<\/jats:italic>. An<jats:italic>in vitro<\/jats:italic>, hepatic I\/R model was used to validate these data. We demonstrate that UnAG upregulates the expression of Cox subunit IV (CoxIV) and increases cellular ATP content. This results in Bcl-2 upregulation and protection against apoptosis. Opa1 silencing shows that Opa1 is crucial for a UnAG-induced increase in cellular ATP content, apoptosis resistance, Bcl-2 and CoxIV expression. Finally, we show that UnAG improves Opa1\u2019s interaction with MIC60 in the I\/R setting, hinting at its role in cristae shape regulation. Our results demonstrate that UnAG administration rescues the intrinsic mitochondrial pathway triggered by I\/R damage. Opa1\u2019s contribution in mediating this effect is also reported. This suggests that UnAG can interfere with mitochondrial dysfunction, via Opa1, in a preclinical liver I\/R model. We therefore provide the rationale for exploiting UnAG as an alternative means to rescuing mitochondrial damage and organ dysfunction.<\/jats:p>","DOI":"10.1038\/cddiscovery.2017.77","type":"journal-article","created":{"date-parts":[[2017,12,4]],"date-time":"2017-12-04T05:02:11Z","timestamp":1512363731000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Unacylated ghrelin prevents mitochondrial dysfunction in a model of ischemia\/reperfusion liver injury"],"prefix":"10.1038","volume":"3","author":[{"given":"Alberto","family":"Rossetti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Togliatto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anabela P","family":"Rolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1244-275X","authenticated-orcid":false,"given":"Jo\u00e3o S","family":"Teodoro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccarda","family":"Granata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezio","family":"Ghigo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amedeo","family":"Columbano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos M","family":"Palmeira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0944-6992","authenticated-orcid":false,"given":"Maria Felice","family":"Brizzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,12,4]]},"reference":[{"key":"BFcddiscovery201777_CR1","doi-asserted-by":"publisher","first-page":"138","DOI":"10.2174\/157340310791658785","volume":"6","author":"EP Soler","year":"2010","unstructured":"Soler EP, Ruiz VC . 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