Molecular Mechanism of Ischemic Renal Failure

描述(由申请人提供)： 肾缺血-再灌注导致急性肾损伤(AKI)，这是一种主要的肾脏疾病，与高死亡率相关，并影响普通人群和退伍军人。缺血性AKI的一个重要病理特征是肾小管细胞的坏死和凋亡。董博士的长期目标是阐明肾小管细胞死亡的机制，并发现预防和治疗AKI的新的、有效的策略。在上一次授予期间，董博士和他的同事揭示了线粒体在凋亡过程中的显著形态变化，称为线粒体碎裂。线粒体断裂的抑制阻止了肾小管的细胞凋亡，并改善了AKI，支持了关键的致病作用。从机制上讲，线粒体碎裂需要同时切割线粒体内膜和外膜。外膜的切割涉及DRP-1的激活和丝裂蛋白的失活；然而，对内膜的切割知之甚少。董博士和他的同事现在已经证明了Bax相互作用因子-1(Bif-1)在线粒体碎裂中的作用。此外，他们还发现了Bif-1与禁止蛋白2(PHB2)的新相互作用，PHB2是一种可能通过隔离OMA1来阻止内膜融合蛋白OPA1的蛋白分解来调节线粒体内膜的蛋白质。基于这些观察，他们假设：在细胞应激过程中，Bif-1移位到线粒体并与PHB2相互作用，导致抑制素环复合体被破坏以释放OMA1。然后，OMA1可以与OPA1进行蛋白水解性切割和失活，导致内膜融合被抑制，从而导致线粒体碎裂。为了验证这一假说，他们将：1)确定Bif-1在缺血性AKI时抑制环复合体断裂、OPA1蛋白降解、线粒体损伤和细胞凋亡中的作用；2)阐明Bif-1和PHB2之间的分子相互作用，并确定其在线粒体调控中的作用；3)确定OMA1在OPA1蛋白降解、线粒体断裂和肾小管细胞凋亡中的作用。这一应用将揭示内膜断裂在线粒体碎裂和细胞凋亡中的分子机制。这也可能导致开发新的治疗策略来治疗缺血性AKI和相关疾病。

DESCRIPTION (provided by applicant): Renal ischemia-reperfusion leads to acute kidney injury (AKI), a major kidney disease that is associated with high mortality and affects both the general population and veterans. A key pathological feature of ischemic AKI is necrotic and apoptotic cell death in renal tubules. The long- term goal of Dr. Dong is to delineate the mechanism of tubular cell death in kidneys and discover new, effective strategies for the prevention and treatment of AKI. During the last grant period, Dr. Dong and colleagues revealed a striking morphological change of mitochondria during apoptosis, called mitochondrial fragmentation. Inhibition of mitochondrial fragmentation prevented apoptosis in renal tubules and ameliorated AKI, supporting a critical pathogenic role. Mechanistically, mitochondrial fragmentation requires the cleavage of both mitochondrial inner and outer membranes. Cleavage of the outer membrane involves the activation of Drp-1 and inactivation of Mitofusins; however, very little is known about cleavage of the inner membrane. Dr. Dong and colleagues have now demonstrated a role of Bax-interacting factor-1 (Bif-1) in mitochondrial fragmentation. Moreover, they have discovered the novel interaction of Bif-1 with prohibitin 2 (PHB2), a protein that may regulate mitochondrial inner membrane by sequestering OMA1 to prevent the proteolysis of OPA1, an inner membrane fusion protein. Based on these observations, they hypothesize that: During cellular stress, Bif-1 translocates to mitochondria and interacts with PHB2, resulting in the disruption of the prohibitin ring complex to release OMA1. OMA1 then has the access to OPA1 for proteolytic cleavage and inactivation, leading to the inhibition of inner membrane fusion to contribute to mitochondrial fragmentation. To test this hypothesis, they will: 1) determine the role of Bif-1 in prohibitin ring complex disruption, OPA1 proteolysis, mitochondrial damage and apoptosis during ischemic AKI; 2) elucidate the molecular interaction between Bif-1 and PHB2, and determine its role in mitochondrial regulation; 3) determine the role of OMA1 in OPA1 proteolysis, mitochondrial fragmentation and tubular cell apoptosis. This application will delineate the molecular mechanism of inner membrane cleavage in mitochondrial fragmentation and apoptosis. It may also lead to the development of novel therapeutic strategies for ischemic AKI and related diseases.