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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Tau is classically defined as a microtubule-associated protein whose dysfunction underpins neurodegenerative disorders. However, its role in cardiac pathophysiology remains elusive despite recent evidence of its cardiac expression. Here, we report that a ~55 kDa Tau-immunoreactive species, which is commonly found in the nervous system, is markedly upregulated in isoproterenol-induced hypertrophic murine hearts, suggesting that this stress-inducible species is associated with maladaptive cardiac remodeling. Forced Tau expression was sufficient to induce hypertrophic growth in cultured cardiomyocytes. Cardiomyocyte-restricted Tau overexpression in transgenic mice recapitulated the progressive trajectory from hypertrophy to overt heart failure. Mechanistically, Tau overexpression triggered excessive mitochondrial fission, leading to mitochondrial dysfunction evidenced by reduced mitochondrial membrane potential, elevated reactive oxygen species, diminished activity of respiratory chain complexes I and IV, and decreased intracellular ATP. Pharmacological inhibition of mitochondrial fission with Mdivi-1 attenuated Tau overexpression-induced cardiomyocyte hypertrophy; taken together, our gain-of-function evidence identifies the ~55 kDa Tau-immunoreactive species as a stress-associated factor that disrupts mitochondrial dynamics to promote cardiac remodeling, and suggests Tau as a potential therapeutic target for cardiac diseases.<\/jats:p>","DOI":"10.3390\/ijms27188075","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T08:17:42Z","timestamp":1789114662000},"page":"8075","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tau\u00a0Overexpression Causes Cardiac Hypertrophy by Disrupting Mitochondrial Homeostasis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7672-8619","authenticated-orcid":false,"given":"Jingping","family":"Xu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8792-9911","authenticated-orcid":false,"given":"Yujia","family":"Xing","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing 102206, China"},{"name":"College of Life Sciences, Hebei University, Baoding 071002, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Qiqi","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing 102206, China"},{"name":"College of Life Sciences, Hebei University, Baoding 071002, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Tianle","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Wenjia","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Xiao","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing 102206, China"},{"name":"College of Life Sciences, Hebei University, Baoding 071002, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6327-9561","authenticated-orcid":false,"given":"Zhenhua","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing 102206, China"},{"name":"College of Life Sciences, Hebei University, Baoding 071002, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing 102206, China"},{"name":"College of Life Sciences, Hebei University, Baoding 071002, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1161\/CIRCRESAHA.124.323800","article-title":"Mitochondrial Structure and Function in Human Heart Failure","volume":"135","author":"Hinton","year":"2024","journal-title":"Circ. 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