| First Author | Wu S | Year | 2017 |
| Journal | Circulation | Volume | 136 |
| Issue | 23 | Pages | 2248-2266 |
| PubMed ID | 28942427 | Mgi Jnum | J:271166 |
| Mgi Id | MGI:6279329 | Doi | 10.1161/CIRCULATIONAHA.117.030235 |
| Citation | Wu S, et al. (2017) 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. Circulation 136(23):2248-2266 |
| abstractText | BACKGROUND: 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. METHODS: The impacts of FUNDC1 on MAMs formation and cardiac functions were studied in mouse neonatal cardiomyocytes, in mice with cardiomyocyte-specific Fundc1 gene knockout (Fundc1(f/Y)/Cre(alphaMyHC+/-) ), and in the cardiac tissues of the patients with heart failure. RESULTS: 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 Ca(2+) in both mitochondria and cytosol, whereas overexpression of Fundc1 increased the levels of IP3R2 and Ca(2+) in both mitochondria and cytosol. Consistently, Fundc1 ablation increased Ca(2+) levels in ER, whereas Fundc1 overexpression lowered ER Ca(2+) levels. Further, Fundc1 ablation in cardiomyocytes elongated mitochondria and compromised mitochondrial functions. Mechanistically, we found that Fundc1 ablation-induced reduction of intracellular Ca(2+) 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. Fundc1(f/Y)/Cre(alphaMyHC+/-) mice but not their littermate control mice (Fundc1(wt/Y)/Cre(alphaMyHC+/-) ) exhibited cardiac dysfunction. The ligation of the left ventricle artery of Fundc1(f/Y)/Cre(alphaMyHC+/-) mice caused more severe cardiac dysfunction than those in sham-treated Fundc1(f/Y)/Cre(alphaMyHC+/-) mice. Finally, we found that the FUNDC1/MAMs/CREB/Fis1 signaling axis was significantly suppressed in patients with heart failure. CONCLUSIONS: We conclude that FUNDC1 binds to IP3R2 to modulate ER Ca(2+) release into mitochondria and cytosol. Further, a disruption of the FUNDC1 and IP3R2 interaction lowers the levels of Ca(2+) in mitochondria and cytosol, both of which instigate aberrant mitochondrial fission, mitochondrial dysfunction, cardiac dysfunction, and heart failure. |
