# Mitochondrial overload and proximal tubular cell atrophy

> **NIH NIH R01** · LSU PENNINGTON BIOMEDICAL RESEARCH CTR · 2020 · $439,560

## Abstract

Proximal tubular epithelial cells (PTC) are highly energy demanding kidney cells. Their energy need is covered
mostly from mitochondrial fatty acid oxidation. If the high energy demand is not met with sufficient ATP
production, tubular epithelial cells undergo apoptosis and atrophy. Derailments in mitochondrial fatty acid
metabolism are therefore the main underlying candidate mechanisms in tubular cell death. It has recently been
discovered in type 2 diabetic mice and humans that the diabetic kidney exhibits increased fatty acid
metabolism and oxidation, but this is not matched with ATP production. The kidney cortex accumulates
incompletely oxidized metabolic products which is typical of mitochondrial overload. Our central hypothesis is
that this incomplete fatty acid oxidation causes proximal tubule apoptosis through pathways critical to
mitochondrial function.
Our compelling set of preliminary data show that mitochondrial overload in cells causes energy deficit and
oxidant production. In our new mouse model, incomplete fatty acid oxidation and mitochondrial overload
causes kidney disease. This was achieved by PTC-specific deletion of carnitine-acetyltransferase (CrAT). The
enzyme shuttles excess fatty acid products out of the mitochondria; therefore, lack of CrAT models
mitochondrial overload. Our goal is to define the mechanisms that are forerunners of tubular apoptosis due to
mitochondrial overload. Three interconnected but independent aims will test our hypothesis using state-of-the-
art approaches of both molecular and redox biology. In Aim 1, we will test the prediction that incomplete fatty
acid oxidation causes mitochondrial energy deficit, which is then detrimental to tubular cells. Aim 2 will test the
hypothesis that incomplete fatty acid oxidation leads to excess mitchondrial ROS production and apoptosis.
The first two aims will use loss-of-function approaches (PTC-specific CrAT knockout mice alone or in
combination with obesity and type 2 diabetes), mechanistic studies from primary PTCs isolated from these
models and advanced biophysical measurements (extracellular flux analyzer, electron spin resonance
spectroscopy). In Aim 3, we will test whether alleviating mitochondrial overload by enhancing the efflux of
incompletely oxidized products offers prevention. We will use in vitro and in vivo gain-of-function experiments
(CrAT overexpression and re-expression) as rescue experiments. The experimental strategy is designed to
establish the role of incomplete mitochondrial fatty acid oxidation in tubular injury, decipher the underlying
biochemical mechanisms and address whether such pathways can offer the basis for tubular cell preservation
well before the appearance of apoptosis, in the context of obesity and type 2 diabetes. Provided that these
mechanisms are forerunners of tubular cell apoptosis, targeting mitochondrial fatty acid overload can be a
prominent new area to prevent, rather than treat tubular atrophy and chronic kidney disea...

## Key facts

- **NIH application ID:** 9944549
- **Project number:** 5R01DK115749-03
- **Recipient organization:** LSU PENNINGTON BIOMEDICAL RESEARCH CTR
- **Principal Investigator:** Krisztian Stadler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $439,560
- **Award type:** 5
- **Project period:** 2018-06-05 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9944549

## Citation

> US National Institutes of Health, RePORTER application 9944549, Mitochondrial overload and proximal tubular cell atrophy (5R01DK115749-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9944549. Licensed CC0.

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