Binding of FUN14 Domain Containing 1 With Inositol 1,4,5-Trisphosphate Receptor in Mitochondria-Associated Endoplasmic Reticulum Membranes Maintains Mitochondrial Dynamics and Function in Hearts in Vivo

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FUN14 domain containing 1 (FUNDC1) is a highly conserved outer mitochondrial membrane protein. The aim of this study is to examine whether FUNDC1 modulates the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), mitochondrial morphology, and function in cardiomyocytes and intact hearts.


The impacts of FUNDC1 on MAMs formation and cardiac functions were studied in mouse neonatal cardiomyocytes, in mice with cardiomyocyte-specific Fundc1 gene knockout (Fundc1f/Y/CreαMyHC+/−), and in the cardiac tissues of the patients with heart failure.


In mouse neonatal cardiomyocytes and intact hearts, FUNDC1 was localized in MAMs by binding to ER-resided inositol 1,4,5-trisphosphate type 2 receptor (IP3R2). Fundc1 ablation disrupted MAMs and reduced the levels of IP3R2 and Ca2+ in both mitochondria and cytosol, whereas overexpression of Fundc1 increased the levels of IP3R2 and Ca2+ in both mitochondria and cytosol. Consistently, Fundc1 ablation increased Ca2+ levels in ER, whereas Fundc1 overexpression lowered ER Ca2+ levels. Further, Fundc1 ablation in cardiomyocytes elongated mitochondria and compromised mitochondrial functions. Mechanistically, we found that Fundc1 ablation-induced reduction of intracellular Ca2+ levels suppressed mitochondrial fission 1 protein (Fis1) expression and mitochondrial fission by reducing the binding of the cAMP response element binding protein (CREB) in the Fis1 promoter. Fundc1f/Y/CreαMyHC+/− mice but not their littermate control mice (Fundc1wt/Y/CreαMyHC+/−) exhibited cardiac dysfunction. The ligation of the left ventricle artery of Fundc1f/Y/CreαMyHC+/− mice caused more severe cardiac dysfunction than those in sham-treated Fundc1f/Y/CreαMyHC+/− mice. Finally, we found that the FUNDC1/MAMs/CREB/Fis1 signaling axis was significantly suppressed in patients with heart failure.


We conclude that FUNDC1 binds to IP3R2 to modulate ER Ca2+ release into mitochondria and cytosol. Further, a disruption of the FUNDC1 and IP3R2 interaction lowers the levels of Ca2+ in mitochondria and cytosol, both of which instigate aberrant mitochondrial fission, mitochondrial dysfunction, cardiac dysfunction, and heart failure.

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