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Optic atrophy 1 (OPA1) and its GTPase activity are involved in maintaining mitochondrial cristae and inner membrane fusion. This study aimed to explore the role of OMA1-mediated OPA1 cleavage (S1-OPA1) in neurons exposed to cerebral ischemia and reperfusion. After oxygen-glucose deprivation (OGD) for 60\u2009min, we found that mitochondrial fragmentation occurred successively in the axon and soma of neurons, accompanied by an increase in S1-OPA1. In addition, S1-OPA1 overexpression significantly aggravated mitochondrial damage in neurons exposed to OGD for 60\u2009min and 24\u2009h after OGD\/R, characterized by mitochondrial fragmentation, decreased mitochondrial membrane potential, mitochondrial cristae ultrastructural damage, increased superoxide production, decreased ATP production and increased mitochondrial apoptosis, which was inhibited by the lysine 301 to alanine mutation (K301A). Furthermore, we performed neuron-specific overexpression of S1-OPA1 in the cerebral cortex around ischemia of middle cerebral artery occlusion\/reperfusion (MCAO\/R) mice. The results further demonstrated in vivo that S1-OPA1 exacerbated neuronal mitochondrial ultrastructural destruction and injury induced by cerebral ischemia-reperfusion, while S1-OPA1-K301 overexpression had no effect. In conclusion, ischemia induced neuronal OMA1-mediated cleavage of OPA1 at the S1 site. S1-OPA1 aggravated neuronal mitochondrial fragmentation and damage in a GTPase-dependent manner, and participated in neuronal ischemia-reperfusion injury.<\/jats:p>","DOI":"10.1038\/s41419-022-04782-0","type":"journal-article","created":{"date-parts":[[2022,4,8]],"date-time":"2022-04-08T17:03:38Z","timestamp":1649437418000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Ischemia-induced cleavage of OPA1 at S1 site aggravates mitochondrial fragmentation and reperfusion injury in neurons"],"prefix":"10.1038","volume":"13","author":[{"given":"Xiang","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiying","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongmou","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanchun","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengquan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0758-1907","authenticated-orcid":false,"given":"Gang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,8]]},"reference":[{"key":"4782_CR1","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1159\/000506396","volume":"54","author":"RV Krishnamurthi","year":"2020","unstructured":"Krishnamurthi RV, Ikeda T, Feigin VL. 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