# Mitonuclear Communication During the Pathogenesis of Inflammatory Bowel Disease

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $352,125

## Abstract

Project Summary/Abstract
An estimated 3.1 million American are currently diagnosed with Inflammatory Bowel Disease (IBD) and
the worldwide incidence of disease is increasing. There is growing appreciation for mitochondrial
dysfunction as a cause of and therapeutic target for inflammatory disease, however mitochondrial health
has been understudied in the intestine. The broad goal of this proposal is to determine how
mitochondrial dysfunction in the intestinal epithelium contributes to IBD pathogenesis and to
investigate whether reversing or preventing mitochondrial dysfunction can improve outcomes.
We evaluated the intestinal epithelium of patients with IBD for protein levels and expression of
Peroxisome Proliferator-activated Receptor-γ Coactivator 1-α (PGC1α), the master regulator protein of
mitochondrial biogenesis, and found evidence of significant downregulation. Intestinal epithelium-specific
PGC1α knockout mice were found to be highly susceptible to an acute intestinal injury model, while
pharmacologic restitution of PGC1α levels rescued mice from inflammation. Recently, we found that
mitophagy is a key adaptive response to mitochondrial damage in the intestine during IBD. In response
to mitochondrial injury, the mitophagy protein Nix is upregulated and moves to the mitochondria where it
binds LC3 and initiates degradation of the affected mitochondria. In parallel to these investigations, we
contributed to an important multi-institutional study detailing a “mitochondriopathy” of pediatric-onset UC
characterized by downregulation of PGC1α and associated genes governing oxidative phosphorylation
and mitochondrial quality control. In fact, this mitochondrial signal was found to be the most
significant hallmark of treatment-naïve pediatric-onset UC. Although a disruption of mitochondrial
dynamics alone likely does not cause IBD, it appears to drive ongoing inflammation within the intestinal
epithelium and may serve as important biomarker of disease. Whether a cause or consequence of
disease, we postulate that the process of mitochondrial dysfunction offers significant opportunity for
therapeutic intervention. Our hypothesis is that the mitochondriopathy of IBD is a signature feature
of disease with important functional consequences, and one that is amenable to therapeutic
targeting. In order to test this hypothesis, we have devised the following aims: Aim 1: To evaluate the
cause of mitochondrial dysfunction during IBD. Aim 2: To characterize the physiologic response
to mitochondrial dysfunction during IBD. Aim 3: To target mitochondrial dysfunction
therapeutically in murine colitis and characterize the metabolic effects of mitochondrial
dysfunction in human IBD. Successful completion of these experiments will frame the causes and
consequences of mitochondrial dysfunction during IBD, offering the opportunity to improve disease
outcomes by mitigating ongoing inflammation.

## Key facts

- **NIH application ID:** 10337233
- **Project number:** 5R01DK120986-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Kevin P Mollen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $352,125
- **Award type:** 5
- **Project period:** 2020-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10337233

## Citation

> US National Institutes of Health, RePORTER application 10337233, Mitonuclear Communication During the Pathogenesis of Inflammatory Bowel Disease (5R01DK120986-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10337233. Licensed CC0.

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