MICU3 Regulates Mitochondrial Calcium and Cardiac Hypertrophy

作者：Bárbara Román, Yusuf Mastoor, Junhui Sun, Hector Chapoy Villanueva, Gabriela Hinojosa, Danielle Springer, Julia Liu, Elizabeth Murphy · 发表于：Circulation Research · 年份：2024 · DOI：10.1161/circresaha.123.324026 · 被引用次数：18 · 研究领域：Mitochondrial Function and Pathology、GDF15 and Related Biomarkers、Cardiomyopathy and Myosin Studies

BACKGROUND: Calcium (Ca 2+ ) uptake by mitochondria occurs via the mitochondrial Ca 2+ uniporter. Mitochondrial Ca 2+ uniporter exists as a complex, regulated by 3 MICU (mitochondrial Ca 2+ uptake) proteins localized in the intermembrane space: MICU1, MICU2, and MICU3. Although MICU3 is present in the heart, its role is largely unknown. METHODS: We used CRISPR-Cas9 to generate a mouse with global deletion of MICU3 and an adeno-associated virus (AAV9) to overexpress MICU3 in wild-type mice. We examined the role of MICU3 in regulating mitochondrial calcium ([Ca 2+ ] m ) in ex vivo hearts using an optical method following adrenergic stimulation in perfused hearts loaded with a Ca 2+ -sensitive fluorophore. Additionally, we studied how deletion and overexpression of MICU3, respectively, impact cardiac function in vivo by echocardiography and the molecular composition of the mitochondrial Ca 2+ uniporter complex via Western blot, immunoprecipitation, and Blue native-PAGE analysis. Finally, we measured MICU3 expression in failing human hearts. RESULTS: MICU3 knock out hearts and cardiomyocytes exhibited a significantly smaller increase in [Ca 2+ ] m than wild-type hearts following acute isoproterenol infusion. In contrast, heart with overexpression of MICU3 exhibited an enhanced increase in [Ca 2+ ] m compared with control hearts. Echocardiography analysis showed no significant difference in cardiac function in knock out MICU3 mice relative to wild-type mice at baseline. However, m...