A novel mechanism of mitochondrial protein turnover in Complex I deficient mitochondrial cardiomyopathy

项目总结 线粒体是活性氧(ROS)的重要来源。曾经认为它本质上是坏的 可引起氧化损伤，是生理性ROS产生的重要信号分子。复数i of 线粒体是ROS产生的重要来源，功能失调的复合体I与 线粒体疾病和成人起病的代谢性、神经退行性疾病、癌症和心脏疾病。在……里面 事实上，复杂的i功能障碍是代谢表现中最常见的先天错误，通常会导致 儿童线粒体心肌病。我们的实验室一直在研究线粒体的小鼠模型 心肌病，以发现在复合体I损伤期间保持生物能量平衡的机制。 在研究线粒体钙单转运体(MCU)的过程中，线粒体钙单一转运体(MCU)是ATP合成的重要调节因子。 复杂的I功能障碍，我们发现了一种新的形式的ROS依赖的蛋白质调节。我们发现这是在 正常情况下，MCU与复合体I瞬间相互作用，并在体内产生生理ROS 复杂的I导致MCU的更替。然而，在复杂的i功能障碍期间，复杂的i-MCU相互作用是 取消后，MCU的寿命增加，而这种延长的寿命有助于保护线粒体的生物能量 动态平衡。我们将这种机制称为复杂的I诱导蛋白周转(CLIPT)，并假设 CLIPT是一种更普遍的现象，适用于其他线粒体蛋白。 这项提议的目的是确定CLIPT是否是一种使线粒体蛋白质能够 补偿心肌线粒体动态平衡的破坏。在初步的屏幕中，我们展示了一个 一系列线粒体蛋白可能同样受到CLIPT的影响，但对于本提案，我将重点介绍两个 感兴趣的蛋白质：过氧化还蛋白3(PRDX3)和羟基类固醇17-β脱氢酶(HSD17B10)。 PRDX3和HSD17B10在ROS诱导的蛋白质周转过程中是有趣的候选基因 分别在抗氧化系统和脂肪酸新陈代谢中发挥作用。在目标1中，我将演示如何 PRDX3和HSD17B10也通过CLIPT进行调节，在目标2中，定义了与 在复杂的I功能障碍背景下PRDX3和HSD17B10的上调。我们的结果可能会提供新的 心脏线粒体疾病治疗的靶点。

PROJECT SUMMARY Mitochondria are an important source of reactive oxygen species (ROS). Once thought of inherently bad as it can cause oxidative damage, physiological ROS production is an important signaling molecule. Complex I of the mitochondria is an important source of ROS production and dysfunctional Complex I has been implicated in both mitochondrial disease and in adult-onset metabolic, neurodegenerative, cancer, and cardiac diseases. In fact, Complex I dysfunction is the most common inborn error of metabolism manifests, often resulting in pediatric mitochondrial cardiomyopathies. Our lab has been studying a mouse model of mitochondrial cardiomyopathies to discover mechanisms preserving bioenergetic homeostasis during Complex I impairment. In studying the mitochondrial calcium uniporter (MCU), an important regulator of ATP synthesis, during Complex I dysfunction, we identified a novel form of ROS-dependent protein regulation. We found that under normal circumstances, MCU transiently interacts with Complex I, and physiological ROS production in Complex I leads to MCU turnover. However, during Complex I dysfunction, the Complex I-MCU interaction is abolished, MCU lifespan increases, and this increased lifespan helps preserve mitochondrial bioenergetic homeostasis. We term this mechanism Complex I-induced protein turnover (CLIPT), and hypothesize that CLIPT is a more widespread phenomenon applicable to other mitochondrial proteins. The objective of this proposal is to determine if CLIPT is a mechanism that enables mitochondrial proteins to compensate for disruptions to cardiac mitochondrial homeostasis. In a preliminary screen, we show that a range of mitochondrial proteins may be similarly subject to CLIPT but for this proposal, I will focus on two proteins of interest: Peroxiredoxin3 (PRDX3) and Hydroxy steroid 17-beta dehydrogenase (HSD17B10). PRDX3 and HSD17B10 are interesting candidates in the setting of ROS-induced protein turnover as they play a role in an antioxidant system and in fatty acid metabolism, respectively. In Aim 1, I will demonstrate how PRDX3 and HSD17B10 is also regulated through CLIPT and in Aim 2, define the clinical relevance to upregulation of PRDX3 and HSD17B10 in the context of Complex I dysfunction. Our results may offer new targets for therapies for cardiac mitochondrial disease.