Mitochondrial electron transport dysfunction: Dissecting pathomechanisms

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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.