NDUFAB1 confers cardio-protection by enhancing mitochondrial bioenergetics through coordination of respiratory complex and supercomplex assembly
NDUFAB1 confers cardio-protection by enhancing mitochondrial bioenergetics through coordination of respiratory complex and supercomplex assembly
复制标题
NDUFAB1 通过协调呼吸复合物和超复合物组装来增强线粒体生物能，从而提供心脏保护作用
DOI：
10.1038/s41422-019-0208-x
复制
发表时间：
2019-09-01
期刊：
影响因子：
44.1
通讯作者：
Wang, Xianhua
中科院分区：
文献类型：
--
作者：
Hou, Tingting;Zhang, Rufeng;Wang, Xianhua
线粒体生物能量学的损伤，通常伴随着活性氧（ROS）的过度产生，是包括心脏在内的能量需求高的器官的基本疾病机制。建立一个更强健、更安全的细胞发电站有望在压力条件下保护这些器官。在这里，我们证明了NADH：泛醌氧化还原酶亚基AB1 (NDUFAB1)，也被称为线粒体酰基载体蛋白，通过赋予线粒体能量代谢更大的能力和效率，作为一种强大的心脏保护者。特别是NDUFAB1不仅作为配合物I亚基，还通过调节铁硫生物合成和配合物I亚基稳定性，协调呼吸配合物I、II、III和超配合物的组装。ndufab1在小鼠心脏特异性缺失引起生物能量学缺陷和ROS水平升高，导致进行性扩张性心肌病和最终的心力衰竭和猝死。过表达ndufab1可有效增强线粒体生物能量，同时限制ROS的产生，保护心脏免受缺血再灌注损伤。总之，我们的研究结果表明，NDUFAB1通过协调呼吸复合物和超复合物的组装，是线粒体能量和ROS代谢的重要调节因子，因此为预防和治疗心力衰竭提供了潜在的治疗靶点。
The impairment of mitochondrial bioenergetics, often coupled with exaggerated reactive oxygen species (ROS) production, is a fundamental disease mechanism in organs with a high demand for energy, including the heart. Building a more robust and safer cellular powerhouse holds the promise for protecting these organs in stressful conditions. Here, we demonstrate that NADH:ubiquinone oxidoreductase subunit AB1 (NDUFAB1), also known as mitochondrial acyl carrier protein, acts as a powerful cardio-protector by conferring greater capacity and efficiency of mitochondrial energy metabolism. In particular, NDUFAB1 not only serves as a complex I subunit, but also coordinates the assembly of respiratory complexes I, II, and III, and supercomplexes, through regulating iron-sulfur biosynthesis and complex I subunit stability. Cardiac-specific deletion ofNdufab1in mice caused defective bioenergetics and elevated ROS levels, leading to progressive dilated cardiomyopathy and eventual heart failure and sudden death. Overexpression ofNdufab1effectively enhanced mitochondrial bioenergetics while limiting ROS production and protected the heart against ischemia-reperfusion injury. Together, our findings identify that NDUFAB1 is a crucial regulator of mitochondrial energy and ROS metabolism through coordinating the assembly of respiratory complexes and supercomplexes, and thus provide a potential therapeutic target for the prevention and treatment of heart failure.