{"title":"脱氨酸α-微管蛋白介导射血分数保留心衰患者线粒体功能障碍和舒张功能损害。","authors":"Shunsuke Miura, Tomofumi Misaka, Toranosuke Sekine, Ryo Ogawara, Shohei Ichimura, Yusuke Tomita, Tetsuro Yokokawa, Masayoshi Oikawa, Takafumi Ishida, Yasuchika Takeishi","doi":"10.1002/1873-3468.70119","DOIUrl":null,"url":null,"abstract":"<p>Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, yet its molecular basis remains unclear. Here, we identified detyrosinated α-tubulin as a key cause of mitochondrial dysfunction and impaired mitophagy in HFpEF. In a SAUNA-induced HFpEF mouse model, elevated vasohibin-1 (VASH1) expression was associated with increased detyrosinated α-tubulin. In H9c2 cardiomyocytes, VASH1 overexpression or tubulin tyrosine ligase knockout raised detyrosinated α-tubulin levels, leading to reduced mitochondrial respiration. Detyrosinated α-tubulin on mitochondria impaired Parkin recruitment and polyubiquitination of voltage-dependent anion channel 1, suppressing mitophagy. Cardiac-specific VASH1 expression recapitulated HFpEF-like phenotypes, including diastolic dysfunction, reduced exercise capacity, and decreased mitochondrial complex activity. These findings suggest that α-tubulin detyrosination contributes to HFpEF pathogenesis and may serve as a therapeutic target.</p><p>\n </p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":"599 17","pages":"2474-2490"},"PeriodicalIF":3.0000,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Detyrosinated α-tubulin mediates mitochondrial dysfunction and diastolic impairment in heart failure with preserved ejection fraction\",\"authors\":\"Shunsuke Miura, Tomofumi Misaka, Toranosuke Sekine, Ryo Ogawara, Shohei Ichimura, Yusuke Tomita, Tetsuro Yokokawa, Masayoshi Oikawa, Takafumi Ishida, Yasuchika Takeishi\",\"doi\":\"10.1002/1873-3468.70119\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, yet its molecular basis remains unclear. Here, we identified detyrosinated α-tubulin as a key cause of mitochondrial dysfunction and impaired mitophagy in HFpEF. In a SAUNA-induced HFpEF mouse model, elevated vasohibin-1 (VASH1) expression was associated with increased detyrosinated α-tubulin. In H9c2 cardiomyocytes, VASH1 overexpression or tubulin tyrosine ligase knockout raised detyrosinated α-tubulin levels, leading to reduced mitochondrial respiration. Detyrosinated α-tubulin on mitochondria impaired Parkin recruitment and polyubiquitination of voltage-dependent anion channel 1, suppressing mitophagy. Cardiac-specific VASH1 expression recapitulated HFpEF-like phenotypes, including diastolic dysfunction, reduced exercise capacity, and decreased mitochondrial complex activity. These findings suggest that α-tubulin detyrosination contributes to HFpEF pathogenesis and may serve as a therapeutic target.</p><p>\\n </p>\",\"PeriodicalId\":12142,\"journal\":{\"name\":\"FEBS Letters\",\"volume\":\"599 17\",\"pages\":\"2474-2490\"},\"PeriodicalIF\":3.0000,\"publicationDate\":\"2025-07-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"FEBS Letters\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://febs.onlinelibrary.wiley.com/doi/10.1002/1873-3468.70119\",\"RegionNum\":4,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"Biochemistry, Genetics and Molecular Biology\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"FEBS Letters","FirstCategoryId":"99","ListUrlMain":"https://febs.onlinelibrary.wiley.com/doi/10.1002/1873-3468.70119","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Biochemistry, Genetics and Molecular Biology","Score":null,"Total":0}
Detyrosinated α-tubulin mediates mitochondrial dysfunction and diastolic impairment in heart failure with preserved ejection fraction
Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, yet its molecular basis remains unclear. Here, we identified detyrosinated α-tubulin as a key cause of mitochondrial dysfunction and impaired mitophagy in HFpEF. In a SAUNA-induced HFpEF mouse model, elevated vasohibin-1 (VASH1) expression was associated with increased detyrosinated α-tubulin. In H9c2 cardiomyocytes, VASH1 overexpression or tubulin tyrosine ligase knockout raised detyrosinated α-tubulin levels, leading to reduced mitochondrial respiration. Detyrosinated α-tubulin on mitochondria impaired Parkin recruitment and polyubiquitination of voltage-dependent anion channel 1, suppressing mitophagy. Cardiac-specific VASH1 expression recapitulated HFpEF-like phenotypes, including diastolic dysfunction, reduced exercise capacity, and decreased mitochondrial complex activity. These findings suggest that α-tubulin detyrosination contributes to HFpEF pathogenesis and may serve as a therapeutic target.
期刊介绍:
FEBS Letters is one of the world''s leading journals in molecular biology and is renowned both for its quality of content and speed of production. Bringing together the most important developments in the molecular biosciences, FEBS Letters provides an international forum for Minireviews, Research Letters and Hypotheses that merit urgent publication.