Mitochondrial electron transport dysfunction: Dissecting pathomechanisms

线粒体(Mt)电子传递失调是公认的衰老特征。 促进细胞损伤、炎症和器官纤维化。很多慢性病， 包括慢性肾脏疾病，都与线粒体电子传递功能障碍有关， 强调了它在器官发病中的重要性。除了通过电子产生ATP之外 运输相关的氧化磷酸化，线粒体作为信号细胞器工作，在 哪种电子传递与包括三羧酸在内的多种代谢途径相交 酸(TCA)循环、氨基酸、脂肪酸、葡萄糖和一碳代谢。此外，芒特山 电子传递产生作为信号分子的活性氧物种(ROS) 调节重要的细胞通路，如低氧诱导因子(HIF)依赖 氧气感应。虽然与许多与年龄相关的慢性疾病高度相关，但在体内 研究线粒体电子传递功能障碍的机制 器官发病机制因缺乏适当的遗传动物模型而变得混乱。在……里面 特别是，mt电子传递与TCA循环代谢和 它们对衰老和慢性病发展的影响还不完全清楚。这个 这项探索性研究资助申请的重点是开发和表征 解决这些知识缺陷的新型遗传小鼠模型。 我们的实验室已经证明，肾脏中MT电子传递的中断抑制了TCA循环 通量、氨基酸代谢和大分子合成，对分化和 肾上皮细胞以肾单位段特异性方式增殖。在这笔赠款下，我们 建立肾单位节段特异的基因敲除模型，以剖析Mt 电子传递失调会促进肾脏损伤和纤维化。具体地说，我们专注于 线粒体电子传递依赖的TCA循环功能障碍在肾脏发病中的作用。 在目标1下，我们描述了mt电子传递的肾单位节段特有的遗传模型。 线粒体泛喹酚-细胞色素c还原酶复合体VII亚单位失活所致的破坏 (MT复合体III)，即泛醌结合蛋白Q结合蛋白QPC。在……下面 目的2.在qpc缺陷的肾脏，我们重新激活mt电子通量，恢复tca循环功能。 一种选择性电子传递氧化酶在上皮细胞中的特异性表达 (AOX)。该模型将用于表征三氯乙酸循环失调的致病作用。 在肾上皮细胞中，由于线粒体复合体III的破坏而导致线粒体功能障碍。

Dysregulation of mitochondrial (mt) electron transport is a well-recognized feature of the aging process and promotes cellular injury, inflammation, and organ fibrosis. Many chronic diseases, including chronic kidney diseases, are associated with mt electron transport dysfunction, underscoring its importance in organ pathogenesis. In addition to ATP production via electron transport-linked oxidative phosphorylation, mitochondria operate as signaling organelles, in which electron transport intersects with multiple metabolic pathways including the tricarboxylic acid (TCA) cycle, amino acid, fatty acid, glucose and one carbon metabolism. Furthermore, mt electron transport generates reactive oxygen species (ROS), which act as signaling molecules that regulate important cellular pathways, such as hypoxia-inducible factor (HIF)-dependent oxygen sensing. Although highly relevant to many age-related and chronic diseases, in vivo studies investigating the mechanisms by which mt electron transport dysfunction contributes to organ pathogenesis have been confounded by the lack of adequate genetic animal models. In particular, the interconnections between mt electron transport and TCA cycle metabolism and their impact on aging and chronic disease development are only incompletely understood. The focus of this exploratory research grant application is on the development and characterization of novel genetic mouse models that address these knowledge deficits. Our laboratory has shown that mt electron transport disruption in kidney suppresses TCA cycle flux, amino acid metabolism and synthesis of macromolecules, impacting on differentiation and proliferation of renal epithelial cells in a nephron-segment specific manner. Under this grant we develop nephron segment-specific knock-out models to dissect the mechanisms by which mt electron transport dysregulation promotes kidney injury and fibrosis. Specifically, we focus on the role of mt electron transport-dependent TCA cycle dysfunction in kidney pathogenesis. Under aim 1, we characterize nephron segment-specific genetic models of mt electron transport disruption due to inactivation of subunit VII of the mt ubiquinol-cytochrome c reductase complex (mt complex III), which is known as ubiquinone-binding protein Q-binding protein QPC. Under aim 2, we reactivate mt electron flux and restore TCA cycle function in Qpc-deficient renal epithelial cells by cell type-specific expression of an alternative electron-transporting oxidase (AOX). This model will be used to characterize the pathogenic role of TCA cycle dysregulation in renal epithelial cells with mt dysfunction due to mt complex III disruption.