缺血性AKI中肾小管上皮细胞线粒体内膜断裂的分子机制

Acute kidney injury (AKI) is a major kidney disease associated with poor prognosis and high mortality. Ischemia-reperfusion injury is a major cause of AKI, which is pathologically characterized by proximal tubular damage including necrosis and apoptosis. Our research in the last few years has demonstrated that the disruption of mitochondrial dynamics leads to mitochondrial fragmentation, resulting in renal tubular apoptosis during AKI. Thus far, the research of mitochondrial dynamics has been focused on the outer membrane of mitochondria, very little is known about the regulation of the inner membrane. Our preliminary studies suggest that during apoptosis, Bif-1 binds to prohibitin-2, which may disrupt the "prohibitin ring" to release OMA1 to further proteolyze the mitochondrial inner membrane fusion protein OPA1, resulting in inner membrane cleavage. This project will delineate the Bif1/PHB2 interaction and its pathological role, and use gene knockout mouse models to determine the roles of Bif-1 and OMA1 in ischemic AKI and their regulation of mitochondria. Together the research will reveal the regulatory mechanism of mitochondrial inner membrane, opening a new research area of mitochondrial dynamics and its pathological function. It will also build a foundation for the development of targeted therapeutics for AKI。

急性肾损伤（简称AKI）是一种重要的肾脏疾病，预后差，死亡率高。其主要诱因包括肾脏缺血再灌注，病理特征为肾近端小管细胞的坏死与凋亡。本课题组已证实：线粒体动力学紊乱引发线粒体断裂，促进近端小管细胞凋亡，在AKI发病机制中起关键作用。至今，线粒体动力学的研究集中在外膜，而对内膜的调控知之甚少。我们的预实验提示：在细胞凋亡中， Bif-1与prohibitin-2发生分子结合，可能打破prohibitin分子环并从中释放OMA1，水解线粒体内膜融合蛋白OPA1，进而促进内膜断裂。本课题将深入阐明Bif-1与PHB2的分子结合及其病理功能，并利用基因敲除小鼠模型阐明Bif-1和OMA1在缺血性AKI中的作用和对线粒体调控的分子机制。这一研究将首次揭示线粒体内膜的调控机制，为线粒体动力学及其病理变化的研究开拓新方向，也为开发AKI治疗的靶向药物奠定基础。

急性肾损伤（AKI）与修复是一个复杂的病理生理过程。线粒体断裂导致肾小管上皮细胞凋亡参与急性肾损伤的发病，它是由多种分子机制介导的外膜和内膜的断裂过程。如今，线粒体动力学的研究集中在外膜，而对内膜断裂的调控目前知之甚少。本项目的中心假说是：缺血性 AKI 时， Bif-1 被激活，进而转位至线粒体与 PHB2 结合，打破prohibitin分子环，释放出蛋白酶 OMA1，水解内膜融合蛋白 OPA-1，导致线粒体内膜断裂和肾小管细胞凋亡。通过研究Bif-1 在缺血性 AKI 中的作用；Bif-1 与 PHB2 结合的分子机制以及OMA1在缺血缺氧处理的小鼠和肾小管上皮细胞中对OPA1水解、线粒体内膜断裂、肾小管上皮细胞凋亡的作用，本课题完成了预定的研究目标。本课题首次揭示了线粒体内膜的调控机制，为线粒体动力学及其病理变化的研究开拓了新方向，也为开发 AKI 治疗的靶向药物奠定了基础。延伸研究还发现PKC介导的自噬在顺铂诱导的肾小管细胞凋亡中起重要作用；发现糖尿病肾病增加对急性肾损伤的敏感性，并与高血糖、P53、线粒体凋亡信号通路有关；进一步阐明了近端小管P53通过调控多种基因的表达参与急性肾损伤病理过程；揭示了HIF-1调节microRNA489和microRNA687参与缺血性肾损伤的发病。受本项目资助共发表SCI论文19篇，其中第一标注的12篇，第二标注7篇。