# Mitochondrial electron transport dysfunction: Dissecting pathomechanisms

> **NIH NIH R21** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $218,750

## Abstract

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.

## Key facts

- **NIH application ID:** 10828915
- **Project number:** 5R21AG082416-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Volker Hans Haase
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $218,750
- **Award type:** 5
- **Project period:** 2023-04-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828915

## Citation

> US National Institutes of Health, RePORTER application 10828915, Mitochondrial electron transport dysfunction: Dissecting pathomechanisms (5R21AG082416-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10828915. Licensed CC0.

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