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ATPAF1 deficiency impairs ATP synthase assembly and mitochondrial respiration
Mitochondrion ( IF 4.4 ) Pub Date : 2021-08-08 , DOI: 10.1016/j.mito.2021.08.005
Zhou Zhou 1 , Kailiang Zhang 1 , Zhiheng Liu 1 , Xu Gao 1 , Kai Huang 2 , Chen Chen 1 , Daowen Wang 1 , Qinglin Yang 3 , Qinqiang Long 4
Affiliation  

ATP11p and ATP12p are two nuclear-encoded mitochondrial chaperone proteins required for assembling the F1Fo-ATP synthase F1 sector. ATPAF1 and ATPAF2 are the mammalian homologs of ATP11p and ATP12p. However, the biochemical and physiological relevance of ATPAF1 and ATPAF2 in animal tissues with high energy-dependence remains unclear. To explore the in vivo role of ATP assembly and the effects of ATP synthase deficiency in animals, we have generated knockout (KO) mouse models of these assembly factors using CRISPR/Cas9 technology. While the Atpaf2-KO mice were embryonically lethal, Atpaf1-KO mice grew to adulthood but with smaller body sizes and elevated blood lactate later in life. We specifically investigated how ATPAF1 deficiency may affect ATP synthase biogenesis and mitochondrial respiration in the mouse heart, an organ highly energy-dependent. Western blots and Blue-Native electrophoresis (BN-PAGE) demonstrated a decreased F1 content and ATP synthase dimers in the Atpaf1-KO heart. Mitochondria from ATPAF1-deficient hearts showed ultrastructural abnormalities with condensed degenerated mitochondria, loss of cristae, and impaired respiratory capacity. ATP synthase deficiency also leads to impaired autophagy and mitochondrial dynamic. Consequently, decreased cardiac function was exhibited in adult Atpaf1-KO mice. The results provide strong support that ATPAF1 is essential for ATP synthase assembly and mitochondrial oxidative phosphorylation, thus playing a crucial role in maintaining cardiac structure and function in animals.



中文翻译:

ATPAF1缺乏会损害ATP合酶组装和线粒体呼吸

ATP11p 和 ATP12p 是组装 F1Fo-ATP 合酶 F1 区段所需的两种核编码线粒体伴侣蛋白。ATPAF1 和 ATPAF2 是 ATP11p 和 ATP12p 的哺乳动物同源物。然而,ATPAF1 和 ATPAF2 在高能量依赖性动物组织中的生化和生理相关性仍不清楚。为了探索ATP 组装的体内作用以及 ATP 合酶缺乏对动物的影响,我们使用 CRISPR/Cas9 技术生成了这些组装因子的敲除 (KO) 小鼠模型。虽然Atpaf2 -KO 小鼠在胚胎上是致命的,但 Atpaf1-KO 小鼠长到成年,但体型较小,后期血乳酸升高。我们专门研究了 ATPAF1 缺乏如何影响小鼠心脏中的 ATP 合酶生物合成和线粒体呼吸,这是一种高度依赖能量的器官。蛋白质印迹和 Blue-Native 电泳 (BN-PAGE) 显示Atpaf1 -KO 心脏中的 F1 含量和 ATP 合酶二聚体降低。来自 ATPAF1 缺陷心脏的线粒体显示出超微结构异常,伴有浓缩退化的线粒体、嵴缺失和呼吸能力受损。ATP 合酶缺乏也会导致自噬和线粒体动力学受损。因此,成人Atpaf1表现出心脏功能下降-KO小鼠。该结果有力地支持了 ATPAF1 对 ATP 合酶组装和线粒体氧化磷酸化至关重要,因此在维持动物心脏结构和功能方面发挥着至关重要的作用。

更新日期:2021-08-17
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