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. Impact statement This study reveals a novel cytoskeletal mechanism linking α‐tubulin detyrosination to mitochondrial dysfunction in heart failure with preserved ejection fraction (HFpEF). Our findings may advance understanding of the pathogenesis of HFpEF and provide new molecular targets for therapeutic strategies aimed at preserving mitochondrial quality control in heart failure.