# Diversity Supplement to R01 Mitochondrial Dysfunction and Mitophagy in Ileitis

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2022 · $46,463

## 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:** 10443329
- **Project number:** 3R01DK117001-05S1
- **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:** $46,463
- **Award type:** 3
- **Project period:** 2019-08-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10443329

## Citation

> US National Institutes of Health, RePORTER application 10443329, Diversity Supplement to R01 Mitochondrial Dysfunction and Mitophagy in Ileitis (3R01DK117001-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10443329. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*