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. Issue 23 (5th December 2017)

• Record Type: Journal Article
• Authors: Wu, Shengnan; Lu, Qiulun; Wang, Qilong; Ding, Ye; Ma, Zejun; Mao, Xiaoxiang; Huang, Kai; Xie, Zhonglin; Zou, Ming-Hui
• Is Part Of: Circulation. Volume 136:Issue 23(2017)
• Publication Date: 2017-12-05
• Subjects: cardiomyopathy -- FUNDC1 -- heart failure -- IP3R2 -- MAMs; Blood -- Circulation -- Periodicals; Cardiovascular system -- Periodicals; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; 616.1
• DOI: 10.1161/CIRCULATIONAHA.117.030235
• Languages: English
• ISSNs: 0009-7322

Abstract

Abstract : 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 αMyHC+/− ), 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 (IP3 R2). Fundc1 ablation disrupted MAMs and reduced the levels of IP3 R2 and Ca 2+ in both mitochondria and cytosol, whereas overexpression of Fundc1 increased the levels of IP3 R2 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 αMyHC+/− mice but not their littermate control mice ( Fundc1 wt/Y /Cre αMyHC+/− ) exhibited cardiac dysfunction. The ligation of the left ventricle artery of Fundc1 f/Y /Cre αMyHC+/− mice caused more severe cardiac dysfunction than those in sham-treated Fundc1 f/Y /Cre αMyHC+/− 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 IP3 R2 to modulate ER Ca 2+ release into mitochondria and cytosol. Further, a disruption of the FUNDC1 and IP3 R2 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. Abstract : Supplemental Digital Content is available in the text.