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（阿基），这是一种与高死亡率相关的主要肾脏疾病，影响普通人群和退伍军人。缺血性阿基的关键病理特征是肾小管中的坏死和凋亡性细胞死亡。Dong博士的长期目标是描绘肾脏中肾小管细胞死亡的机制，并发现预防和治疗阿基的新的有效策略。在上一次资助期间，Dong博士及其同事揭示了细胞凋亡过程中线粒体的惊人形态学变化，称为线粒体碎片化。抑制线粒体断裂可防止肾小管细胞凋亡，并改善阿基，支持关键的致病作用。从机制上讲，线粒体片段化需要线粒体内膜和外膜两者的裂解。外膜的裂解涉及Drp-1的激活和Mitofusins的失活;然而，对内膜的裂解知之甚少。Dong博士及其同事现在已经证明了BIF-1在线粒体片段化中的作用。此外，他们还发现了Bif-1与抑制素2（PHB 2）的新型相互作用，PHB 2是一种蛋白质，可以通过隔离OMA 1来调节线粒体内膜，以防止OPA 1（一种内膜融合蛋白）的蛋白水解。基于这些观察结果，他们假设：在细胞应激期间，Bif-1易位到线粒体并与PHB 2相互作用，导致prohibitin环复合物被破坏以释放OMA 1。然后，OMA 1可以接近OPA 1进行蛋白水解切割和失活，导致内膜融合的抑制，从而促进线粒体片段化。为了验证这一假设，他们将：1）确定Bif-1在缺血性阿基期间抑制素环复合物破坏、OPA 1蛋白水解、线粒体损伤和凋亡中的作用; 2）阐明Bif-1和PHB 2之间的分子相互作用，并确定其在线粒体调节中的作用; 3）确定OMA 1在OPA 1蛋白水解、线粒体片段化和肾小管细胞凋亡中的作用。这一应用将阐明线粒体碎裂和凋亡中内膜裂解的分子机制。它还可能导致缺血性阿基和相关疾病的新治疗策略的开发。

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.