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Mol. Life Sci."],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Diabetic cardiomyopathy (DCM) is a prevalent complication of type 2 diabetes (T2D). 6-phosphofructo-2-kinase\/fructose-2,6-biphosphatase 3 (PFKFB3) is a glycolysis regulator. However, the potential effects of PFKFB3 in the DCM remain unclear. In comparison to db\/m mice, PFKFB3 levels decreased in the hearts of db\/db mice. Cardiac-specific PFKFB3 overexpression inhibited myocardial oxidative stress and cardiomyocyte apoptosis, suppressed mitochondrial fragmentation, and partly restored mitochondrial function in db\/db mice. Moreover, PFKFB3 overexpression stimulated glycolysis. Interestingly, based on the inhibition of glycolysis, PFKFB3 overexpression still suppressed oxidative stress and apoptosis of cardiomyocytes in vitro, which indicated that PFKFB3 overexpression could alleviate DCM independent of glycolysis. Using mass spectrometry combined with co-immunoprecipitation, we identified optic atrophy 1 (OPA1) interacting with PFKFB3. In db\/db mice, the knockdown of OPA1 receded the effects of PFKFB3 overexpression in alleviating cardiac remodeling and dysfunction. Mechanistically, PFKFB3 stabilized OPA1 expression by promoting E3 ligase NEDD4L-mediated atypical K6-linked polyubiquitination and thus prevented the degradation of OPA1 by the\u00a0proteasomal pathway. Our study indicates that PFKFB3\/OPA1 could be potential therapeutic targets for DCM.<\/jats:p>\n                <jats:p><jats:bold>Graphical Abstract<\/jats:bold><\/jats:p>","DOI":"10.1007\/s00018-024-05257-5","type":"journal-article","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T18:02:12Z","timestamp":1716400932000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Cardiac-specific PFKFB3 overexpression prevents diabetic cardiomyopathy via enhancing OPA1 stabilization mediated by K6-linked ubiquitination"],"prefix":"10.1007","volume":"81","author":[{"given":"Jinlan","family":"Luo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuiqing","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingrui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liman","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueting","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menglu","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruolan","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Tu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9041-720X","authenticated-orcid":false,"given":"Xizhen","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,22]]},"reference":[{"key":"5257_CR1","doi-asserted-by":"crossref","unstructured":"Diabetes is a pandemic of unprecedented magnitude now affecting one in 10 adults worldwide. 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