# Elucidating the mechanism of action of novel ClpP activators in activation of the mitochondrial unfolded protein response.

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $314,448

## Abstract

The mitochondrial Unfolded Protein Response (UPRMT) is a highly conserved stress pathway that
when dysregulated is causally connected to a host of degenerative diseases including
Parkinsons, Alzheimers, Freiderichs Ataxia and aging. The recent identification of components
in the UPRMT has stimulated interest in this as a “druggable” pathway. Central to the UPRMT is
the mitochondrial protease ClpP, required for the turnover of damaged and misfolded proteins in
response to cellular stresses. We and others recently identified ClpP as an unexpected target for
a novel class of anti-cancer compounds known as imipridones (ONC201) and related analogs
(https://www.the-scientist.com/news-opinion/found--a-cancer-drugs-mechanism-of-action-
65918). We showed that these compounds activated ClpP and the UPRMT as determined by the
degradation of mitochondrial proteins, impaired mitochondrial respiratory chain activity, and
increased integrated stress response (ISR) proteins (CHOP/ATF4). Thus, the main objective of
this research is to investigate the basic mechanisms of the UPRMT and elucidate how drug-
induced activation of ClpP initiates important stress signals that regulate cell growth and
metabolism. We propose three aims to accomplish this: in Aim 1 we will use comprehensive
proteomics approaches to identify ClpP substrates and peptides released from the mitochondria.
In Aim 2 we will determine how ClpP activation dysregulates mitochondrial metabolism, and
affects the consumption of glucose and glutamine by glycolysis and the TCA cycle. In Aim 3 we
will determine how ClpP activation alters cytosolic signaling events, namely the activation of the
ISR and the resulting reduction in protein synthesis. If successful, our studies will provide
significant new insight into the biological functions of the UPRMT and how ClpP regulates this
pathway functions to modulate cell stress in normal and disease states.

## Key facts

- **NIH application ID:** 10034106
- **Project number:** 1R01GM138520-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Lee M Graves
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $314,448
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10034106

## Citation

> US National Institutes of Health, RePORTER application 10034106, Elucidating the mechanism of action of novel ClpP activators in activation of the mitochondrial unfolded protein response. (1R01GM138520-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10034106. Licensed CC0.

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