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。氧化应激诱导的细胞损伤和死亡发生在缺血/再灌注(I/R)过程中，导致心、脑、肝、肾等不同器官的衰竭。此外，氧化应激通常是药物、毒物和创伤引起的线粒体功能障碍和细胞死亡的媒介。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，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，并在损伤发生后恢复器官功能。细胞通过线粒体的生物发生来取代陈旧和功能失调的线粒体。PGC-11通常被认为是脂肪组织、心脏和肝脏线粒体生物发生的主要调节因子，我们已经证明PGC-11介导了肾近端小管细胞(RPTC)的线粒体生物发生。此外，我们还发现PGC-11的过表达增加了氧化损伤后RPTC中线粒体的生物合成，并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在刺激细胞和器官修复/再生方面有效的假说。我们的初步数据显示，在对照组RPTC和小鼠肾脏中，给予黄烷类化合物会增加PGC-11的水平，并产生线粒体生物发生。初步数据支持我们的假设，即PGC-11是氧化剂和I/R损伤后线粒体生物发生和细胞再生的关键介质，而黄烷类化合物诱导的线粒体生物发生将促进RPTC的再生和损伤后的肾功能。1)阐明PGC-11在RPTC氧化损伤后的调控机制。2)明确类黄酮诱导RPTC线粒体生物发生的机制。3)研究黄烷类化合物诱导的线粒体生物发生对RPTC氧化损伤前后线粒体功能、细胞死亡和再生的影响。4)研究黄酮类化合物对大鼠肾I/R损伤后线粒体生物合成和肾功能恢复的影响。最终，这些研究可能导致新的治疗方法，以提高细胞和器官的存活率和功能，在许多病理情况下。急性肾功能衰竭仍然是一个巨大的公共卫生问题，因为在肾损伤后还没有真正有效的治疗方法被证明是有效的。线粒体生物发生是取代功能障碍的线粒体的过程，为刺激肾损伤后的细胞和器官修复/再生，促进肾功能的恢复提供了一条新的途径。最终，这些研究可能导致新的治疗方法，以提高细胞和器官的存活率和功能，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.