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

项目摘要 线粒体是活性氧的重要来源。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。的复合物i 线粒体是ROS产生的重要来源，功能失调的复合体I与 线粒体疾病和成人发病的代谢、神经变性、癌症和心脏疾病。在 事实上，复合体I功能障碍是最常见的代谢表现的先天性缺陷，通常导致 小儿线粒体心肌病我们的实验室一直在研究一种小鼠模型， 心肌病，以发现在复合物I损伤期间保持生物能量稳态的机制。 在研究线粒体钙单向转运体（MCU），ATP合成的重要调节剂， 复合物I功能障碍，我们确定了一种新的形式的ROS依赖性蛋白质的调节。我们发现， 在正常情况下，MCU与复合物I短暂相互作用，并且在正常情况下， 复合物I导致MCU周转。然而，在复合体I功能障碍期间，复合体I-MCU相互作用是 废除，MCU寿命增加，这种增加的寿命有助于保存线粒体生物能量 体内平衡我们将这种机制称为复合物I诱导的蛋白质周转（CLIPT），并假设 CLIPT是适用于其他线粒体蛋白的更普遍的现象。 该提案的目的是确定CLIPT是否是一种使线粒体蛋白能够 补偿对心脏线粒体稳态的破坏。在初步屏幕中，我们显示， 一系列线粒体蛋白质可能类似地受到CLIPT的影响，但对于这个提议，我将集中在两个方面 感兴趣的蛋白质：过氧化物氧还蛋白3（PRDX 3）和羟基类固醇17-β脱氢酶（HSD 17 B10）。 PRDX 3和HSD 17 B10在ROS诱导的蛋白质周转的背景下是有趣的候选者，因为它们发挥作用。 分别在抗氧化系统和脂肪酸代谢中发挥作用。在目标1中，我将演示如何 PRDX 3和HSD 17 B10也通过CLIPT进行监管，在目标2中，定义了与以下方面的临床相关性： 在复合物I功能障碍的情况下PRDX 3和HSD 17 B10的上调。我们的研究结果可能会提供新的 心脏线粒体疾病的治疗目标。

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.