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.
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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DOI：
10.1161/circulationaha.117.030235
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发表时间：
2017-12-05
期刊：
影响因子：
37.8
通讯作者：
Zou MH
中科院分区：
文献类型：
--
作者：
Wu S;Lu Q;Wang Q;Ding Y;Ma Z;Mao X;Huang K;Xie Z;Zou MH
FUN 14 domain containing 1（FUNDC 1）是一种高度保守的线粒体外膜蛋白。本研究的目的是检测FUNDC 1在心肌细胞和完整心脏中是否调节线粒体相关内质网（ER）膜（MAMs）、线粒体形态和功能。在小鼠新生心肌细胞、心肌细胞特异性Fundc 1基因敲除小鼠（Fundc 1f/Y/CreαMyHC+/−）和心力衰竭患者的心脏组织中研究了Fundc 1对MAMs形成和心脏功能的影响。在小鼠新生心肌细胞和完整心脏中，FUNDC 1通过结合ER-驻留的肌醇1，4，5-三磷酸2型受体（IP 3R 2）定位于MAMs中。Fundc 1消融破坏MAMs，降低线粒体和胞浆中的IP 3R 2和Ca 2+水平，而Fundc 1过表达增加线粒体和胞浆中的IP 3R 2和Ca 2+水平。因此，Fundc 1消融增加ER中的Ca 2+水平，而Fundc 1过表达降低ER Ca 2+水平。此外，心肌细胞中的Fundc 1消融延长了线粒体，并损害了线粒体功能。从机制上讲，我们发现，Fundc 1消融诱导的细胞内Ca 2+水平的降低抑制线粒体裂变1蛋白（Fis 1）的表达和线粒体裂变，减少结合的cAMP反应元件结合蛋白（CREB）在Fis 1启动子。Fundc 1f/Y/CreαMyHC+/−小鼠表现出心功能不全，但其同窝对照小鼠（Fundc 1 wt/Y/CreαMyHC+/−）没有表现出心功能不全。结扎Fundc 1f/Y/CreαMyHC+/−小鼠的左心室动脉导致比假处理的Fundc 1f/Y/CreαMyHC+/−小鼠更严重的心功能障碍。最后，我们发现心力衰竭患者FUNDC 1/MAMs/CREB/Fis 1信号传导轴明显受到抑制。我们的结论是，FUNDC 1结合IP 3R 2调节ER Ca 2+释放到线粒体和胞质溶胶和FUNDC 1和IP 3R 2的相互作用的中断降低线粒体和胞质溶胶中的Ca 2+的水平，这两者都煽动异常线粒体分裂，线粒体功能障碍，心功能障碍和心力衰竭。
FUN14 domain containing 1 (FUNDC1) is a highly conserved outer mitochondrial membrane protein. The aim of this study is to examine if FUNDC1 modulates the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), mitochondrial morphology, and function in cardiomyocytes and in 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, 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 the patients with heart failure. We conclude that FUNDC1 binds to IP3R2 to modulate ER Ca2+ release into mitochondria and cytosol and that a disruption of 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.