# Mitochondrial Dysfunction and Mitophagy in Ileitis

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2022 · $349,323

## Abstract

Project summary
Although mitochondrial dysfunction is demonstrated in the intestinal epithelium of human Crohn's disease (CD)
and ulcerative colitis patients, inflammatory bowel disease (IBD) therapies targeting mitochondrial dysfunction
are currently lacking. It is widely appreciated that the intracellular mitochondrial pool is maintained by removal
of damaged mitochondria via selective autophagy called mitophagy. Mitophagy may be especially important for
the function of intestinal secretory cells (Paneth, goblet, enteroendocrine) which are mitochondria-rich to
sustain energy-expending secretory functions, but this has yet to be demonstrated. Paneth cell dysfunction that
can be driven by autophagy defects is demonstrated in a subset of CD patients. However, the mechanism
whereby mitochondrial stress contributes to inflammation and Paneth cell abnormalities are unknown.
 Prohibitin 1 (PHB1) is the major component protein of the inner mitochondrial membrane (IMM) where it
regulates electron transport chain function important for ATP production. We have generated mice with Villin-
CreERT2 inducible intestinal epithelial cell (IEC)-specific deletion of the PHB1 gene (PHB1∆IEC) and show that
these mice exhibit spontaneous ileitis preceded by mitochondrial dysfunction and Paneth cell defects early
after PHB1 deletion. Paneth cell abnormalities in PHB1∆IEC mice are reminiscent of mice deficient in Paneth cell
autophagy. Our central hypothesis is that mitochondrial dysfunction with subsequent inhibition of mitophagy
caused by loss of PHB1 in the intestinal epithelium leads to Paneth cell dysfunction and ileitis. We will pursue 3
specific aims to test this hypothesis: 1. Define the role of PHB1 in mitochondrial dysfunction and spontaneous
ileitis, 2. Determine the role of PHB1 in mitophagy induction, and 3. Define whether Paneth cells manifest
mitochondrial dysfunction and whether mitochondrial-targeted therapy combats inflammation in patients with
Crohn's ileitis. The long-term objective is to determine whether targeting mitochondrial dysfunction is an
effective therapeutic strategy for IBD.

## Key facts

- **NIH application ID:** 10450818
- **Project number:** 5R01DK117001-06
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** ARIANNE L THEISS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $349,323
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450818

## Citation

> US National Institutes of Health, RePORTER application 10450818, Mitochondrial Dysfunction and Mitophagy in Ileitis (5R01DK117001-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10450818. Licensed CC0.

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