Li Chengfei, Pan Yikai, Tan Yingjun, Wang Yongchun, Sun Xiqing
Department of Aerospace Medical Training, School of Aerospace Medicine, Fourth Military Medical University, Xi'an, China.
China Astronaut Research and Training Center, Beijing, China.
Front Cell Dev Biol. 2022 Jul 7;10:896014. doi: 10.3389/fcell.2022.896014. eCollection 2022.
The effect of cardiovascular dysfunction including orthostatic intolerance and disability on physical exercise is one of the health problems induced by long-term spaceflight astronauts face. As an important part of vascular structure, the vascular endothelium, uniquely sensitive to mechanical force, plays a pivotal role in coordinating vascular functions. Our study found that simulated microgravity induced PINK1-dependent mitophagy in human umbilical vein endothelial cells (HUVECs). Here, we explored the underlying mechanism of mitophagy induction. The ER stress induced by proteostasis failure in HUVECs promoted the Ca transfer from ER to mitochondria, resulting in mitochondria Ca overload, decreased mitochondrial membrane potential, mitochondria fission, and accumulation of Parkin and p62 in mitochondria and mitophagy under simulated microgravity. Moreover, we assumed that mitophagy played a vital role in functional changes in endothelial cells under simulated microgravity. Using mdivi-1 and PINK1 knockdown, we found that NLRP3 inflammasome activation was enhanced after mitophagy was inhibited. The NLRP3 inflammasome contributed to endothelial hyperpermeability and cellular migration by releasing IL-1β. Thus, mitophagy inhibited cell migration ability and hyperpermeability in HUVECs exposed to clinostat-simulated microgravity. Collectively, we here clarify the mechanism of mitophagy induction by simulated microgravity and demonstrate the relationship between mitophagy and vascular endothelial functional changes including cellular migration and permeability. This study deepens the understanding of vascular functional changes under microgravity.
心血管功能障碍（包括体位性不耐受和功能残疾）对体育锻炼的影响是长期太空飞行的宇航员所面临的健康问题之一。作为血管结构的重要组成部分，血管内皮对机械力具有独特的敏感性，在协调血管功能方面起着关键作用。我们的研究发现，模拟微重力可诱导人脐静脉内皮细胞（HUVECs）中依赖PINK1的线粒体自噬。在此，我们探讨了线粒体自噬诱导的潜在机制。HUVECs中蛋白质稳态失衡诱导的内质网应激促进了钙离子从内质网向线粒体的转移，导致线粒体钙超载、线粒体膜电位降低、线粒体裂变，以及Parkin和p62在线粒体中的积累和模拟微重力下的线粒体自噬。此外，我们推测线粒体自噬在模拟微重力下内皮细胞的功能变化中起着至关重要的作用。使用mdivi-1和PINK1基因敲低，我们发现线粒体自噬被抑制后NLRP3炎性小体激活增强。NLRP3炎性小体通过释放IL-1β导致内皮细胞高通透性和细胞迁移。因此，线粒体自噬抑制了暴露于回转器模拟微重力下的HUVECs的细胞迁移能力和高通透性。总的来说，我们在此阐明了模拟微重力诱导线粒体自噬的机制，并证明了线粒体自噬与包括细胞迁移和通透性在内的血管内皮功能变化之间的关系。这项研究加深了对微重力下血管功能变化的理解。
