Mitochondrial Biogenesis Promotes Recovery From Oxidant Injury

描述（由申请人提供）：该项目的长期目标是确定急性器官衰竭的药物治疗方法。氧化应激引起的细胞损伤和死亡发生在缺血/再灌注（I/R）过程中，导致心脏、大脑、肝脏和肾脏等不同器官的衰竭。此外，氧化应激通常是药物、毒物和创伤诱导的线粒体功能障碍和细胞死亡的中介。线粒体功能障碍和相关的ATP耗竭导致细胞损伤和死亡。不幸的是，目前还没有真正有效的治疗方法可以促进细胞和器官的修复/再生，以及器官功能在损伤发生后的恢复。细胞通过线粒体生物发生取代老化和功能失调的线粒体。过氧化物酶体增殖体激活受体γ共激活因子-11 （PGC-11）通常被认为是脂肪组织、心脏和肝脏中线粒体生物发生的主要调节因子，我们已经证明PGC-11介导肾近端小管细胞（RPTC）的线粒体生物发生。此外，我们发现PGC-11的过表达增加了氧化损伤后RPTC中线粒体的生物发生，加速了细胞功能的恢复。这些令人兴奋的结果支持了损伤后线粒体生物发生可能有效刺激细胞和器官修复/再生的假设。我们的初步数据显示，在对照RPTC和小鼠肾脏中，类黄酮的使用增加了PGC-11水平，并产生了线粒体生物生成。初步数据支持我们的假设，即PGC-11是氧化损伤和I/R损伤后线粒体生物发生和细胞再生的关键介质，黄酮诱导的线粒体生物发生将促进损伤后RPTC的再生和肾功能。以下具体目的将验证这些假设：1)阐明氧化损伤后RPTC中PGC-11的调控机制。2)确定黄酮类化合物诱导RPTC线粒体生物发生的机制。3)测定黄酮诱导线粒体生物发生对氧化损伤前后RPTC线粒体功能、细胞死亡和再生的影响。4)确定a类黄酮对I/R损伤后线粒体生物发生和加速肾功能恢复的影响。最终，这些研究可能会导致新的治疗方法，以增加细胞和器官的生存和功能在许多病理情况下。急性肾衰竭仍然是一个巨大的公共卫生问题，因为没有真正有效的治疗方法被证明是有用的肾损伤后。线粒体生物发生是替代功能失调线粒体的过程，为刺激肾损伤后细胞和器官修复/再生，促进肾功能恢复提供了一条新的途径。最终，这些研究可能会导致新的治疗方法，以增加细胞和器官的生存和功能在许多病理情况下。

DESCRIPTION (provided by applicant): The long-term goal of this project is to identify pharmacological treatments for acute organ failure. Cell injury and death induced by oxidative stress occur during ischemia/reperfusion (I/R), leading to failure of different organs such as the heart, brain, liver, and kidneys. Furthermore, oxidative stress is often the mediator of drug-, toxicant-, and trauma-induced mitochondrial dysfunction and cell death. Mitochondrial dysfunction and associated ATP depletion leads to cell injury and death. Unfortunately, there are no truly effective therapies that can promote cell and organ repair/regeneration, and the return of organ function after injury has occurred. Cells replace old and dysfunctional mitochondria through mitochondrial biogenesis. Peroxisome proliferator-activated receptor gamma coactivator-11 (PGC-11) is generally thought to be the master regulator of mitochondrial biogenesis in adipose tissue, heart, and liver, and we have shown that PGC-11 mediates mitochondrial biogenesis in renal proximal tubular cells (RPTC). Furthermore, we showed that over- expression of PGC-11 increases mitochondrial biogenesis in RPTC after oxidant injury and accelerated recovery of cellular functions. These exciting results support the hypothesis that post-injury mitochondrial biogenesis may be efficacious in stimulating cell and organ repair/regeneration. Our preliminary data revealed that administration of a flavanoid increases PGC-11 levels and produces mitochondrial biogenesis in control RPTC and in the mouse kidney. The preliminary data support our hypotheses that PGC-11 is a key mediator of mitochondrial biogenesis and cell regeneration after oxidant and I/R injury, and flavanoid-induced mitochondrial biogenesis will promote regeneration of RPTC and kidney function after injury. The following Specific Aims will test these hypotheses: 1) Elucidate the mechanisms of PGC-11 regulation after oxidant injury in RPTC. 2) Determine the mechanism flavanoid-induced mitochondrial biogenesis in RPTC. 3) Determine the effect of flavanoid-induced mitochondrial biogenesis on mitochondrial function, and cell death and regeneration before and after oxidant injury in RPTC. 4) Determine the effect of a flavanoid on mitochondrial biogenesis and the acceleration of recovery of renal function after I/R injury. Ultimately, these studies may lead to new therapeutic approaches to increase cell and organ survival and function in numerous pathologic situations. Acute renal failure remains an enormous public health concern as no truly effective therapies have proven to be useful after renal injury. Mitochondrial biogenesis, the process of replacing dysfunctional mitochondria, presents a novel avenue for stimulating cell and organ repair/regeneration after renal injury, promoting the return of renal function. Ultimately, these studies may lead to new therapeutic approaches to increase cell and organ survival and function in numerous pathologic situations.