Department of Neurobiology, Key Laboratory of Human Functional Genomics of Jiangsu Province, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China.
Department of Neurobiology, Key Laboratory of Human Functional Genomics of Jiangsu Province, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China; Child Mental Health Research Center, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Biochim Biophys Acta Mol Cell Res. 2023 Aug;1870(6):119487. doi: 10.1016/j.bbamcr.2023.119487. Epub 2023 May 19.
Mitochondrial protein homeostasis is fine-tuned by diverse physiological processes such as mitochondria-associated degradation (MAD), which is regulated by valosin-containing protein (VCP) and its cofactors. As a cofactor of VCP, the mutation of phospholipase A-2-activating protein (PLAA) is the genetic cause of PLAA-associated neurodevelopmental disorder (PLAAND). However, the physiological and pathological roles of PLAA in mitochondria remain unclear. Here, we demonstrate that PLAA partially associates with mitochondria. Deficiency in PLAA increases mitochondrial reactive oxygen species (ROS) production, reduces mitochondrial membrane potential, inhibits mitochondrial respiratory activity and causes excessive mitophagy. Mechanically, PLAA interacts with myeloid cell leukemia-1 (MCL1) and facilitates its retro-translocation and proteasome-dependent degradation. The upregulation of MCL1 promotes the oligomerization of NLR family member X1 (NLRX1) and activation of mitophagy. Whereas downregulating NLRX1 abolishes MCL1 induced mitophagy. In summary, our data identify PLAA as a novel mediator of mitophagy by regulating MCL1-NLRX1 axis. We propose mitophagy as a target for therapeutic intervention in PLAAND.
线粒体蛋白稳态是由多种生理过程精细调控的，如线粒体相关降解（MAD），其受含缬氨酸的蛋白（VCP）及其辅助因子调控。作为 VCP 的辅助因子，磷酸酶 PLA2 激活蛋白（PLAA）的突变是 PLA2 相关神经发育障碍（PLAAND）的遗传原因。然而，PLAA 在线粒体中的生理和病理作用尚不清楚。在这里，我们证明 PLAA 部分与线粒体结合。PLAA 缺乏会增加线粒体活性氧（ROS）的产生，降低线粒体膜电位，抑制线粒体呼吸活性，并导致过度的线粒体自噬。在机制上，PLAA 与髓样细胞白血病-1（MCL1）相互作用，并促进其逆向易位和蛋白酶体依赖性降解。MCL1 的上调促进 NLR 家族成员 X1（NLRX1）的寡聚化和线粒体自噬的激活。而下调 NLRX1 则会消除 MCL1 诱导的线粒体自噬。总之，我们的数据确定了 PLAA 作为一种通过调节 MCL1-NLRX1 轴来介导线粒体自噬的新介质。我们提出线粒体自噬是 PLAAND 治疗干预的一个靶点。
