# The role of mitochondrial stress response in alcohol-mediated neurotoxicity

> **NIH NIH R21** · ROSALIND FRANKLIN UNIV OF MEDICINE & SCI · 2023 · $185,250

## Abstract

Chronic, excessive alcohol use causes regional structural brain damage and cognitive disorders. Chronic
alcohol misuse is also associated with a wide array of movement impairments. Chronic alcohol consumption
alone, or together with alcoholic hepatic encephalopathy, can cause various types of tremor, asterixis, and
cerebellar dysfunction. While alcohol-induced brain damage has been explained by alcohol’s effects on neural
excitability or nutritional deficiency, we do not fully understand the pathogenic mechanism at the molecular and
cellular levels by which alcohol exerts its toxicity and damages the nervous system. The nematode C. elegans
is an amenable model organism that can be used for dissecting the pathological mechanism of alcoholic
neurotoxicity. Our study in C. elegans shows that while alcohol strongly induces many conserved cellular
stress responses, its main toxic effects are centered on mitochondrial function. Remarkably, we find that
perpetual mitochondrial unfolded protein response (UPRmt) spares from a motor function deficit caused by
chronic alcohol exposure. Moreover, a genetic manipulation that specifically induces neuron-specific UPRmt
activation is sufficient to protect against alcohol-mediated movement impairment. We hypothesize that
activation of a branch of UPRmt in a select neural population protects against alcoholic movement disorders. To
test this hypothesis, we propose two specific aims: aim 1 will investigate how perpetual UPRmt protects against
alcohol-mediated movement impairment; and aim 2 will identify the mechanism by which neuronal UPRmt leads
to the protection against alcohol-mediated movement impairment. A detailed analysis of alcohol-mediated
UPRmt and its intra- and intercellular signaling in the context of alcohol-mediated movement impairment will
lead to effective druggable targets that protect against, or ameliorate, alcoholic movement impairment.

## Key facts

- **NIH application ID:** 10708781
- **Project number:** 5R21AA029811-02
- **Recipient organization:** ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
- **Principal Investigator:** Hongkyun Kim
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $185,250
- **Award type:** 5
- **Project period:** 2022-09-25 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10708781

## Citation

> US National Institutes of Health, RePORTER application 10708781, The role of mitochondrial stress response in alcohol-mediated neurotoxicity (5R21AA029811-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10708781. Licensed CC0.

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