# Mitochondrial stress in liver function and dysfunction

> **NIH NIH R56** · AUGUSTA UNIVERSITY · 2023 · $438,900

## Abstract

Project Summary
The liver is responsible for the multitude of processes, notably the metabolic homeostasis and detoxification.
Mitochondria are critical for the metabolic function of the liver and, thus, mitochondrial dysfunction is a major
cause for liver diseases. As the liver is constantly exposed to harmful substances from metabolism and drug
processing, liver mitochondria are especially susceptible to functional impairment. We propose that maintaining
functional mitochondria under the stressful environment will be a key to the long-term preservation of liver health.
The mitochondrial fusion protein optic atrophy 1 (OPA1) is essential for proper function of mitochondria, and the
OPA1 gene knockout (KO) in major organs impairs mitochondrial energetics and causes animal death. However,
we observed that, despite the important role of mitochondria in the liver, liver-specific OPA1-KO mice are healthy
and maintain normal mitochondrial and liver functions. Liver is a resilient organ that has high regenerative
capacity after injury. While OPA1-KO livers do not show any injury, we found that OPA1 KO induces a robust
and efficient integrated stress response (ISR) to preserve liver function, indicating that the ISR is another
mechanism of liver resiliency. These observations suggest that the liver successfully handles the stress induced
by OPA1 KO, providing the important experimental system for mechanistic understanding of the ISR as the
mechanism of liver resiliency. In this proposal, we will elucidate the OPA1 function in the liver, define the
mechanism of how liver handles the mitochondrial stress evoked by the lack of OPA1 function, and test the
feasibility of utilizing the liver ISR for a protective strategy in drug-induced liver injury. Our preliminary data
indicate that the liver has a unique mechanism for ISR through a novel regulation of the critical transcription
factor ATF4. We also discovered a new role of OPA1 as an assembly factor for respiratory complex V, and found
that accumulation of assembly intermediates of complex V evokes mitochondrial stress for the ISR induction. In
this proposal, therefore, we will test our Central Hypothesis that OPA1 is a novel assembly factor for the
respiratory complex V, and its absence in the liver induces the ISR, which prevents liver injury and serves as a
mechanism of the liver resiliency. We will test this hypothesis by three specific aims: (1) to define the unique
mechanism regulating ATF4 in the liver ISR induced by OPA1 KO, (2) to elucidate the new role of OPA1 as a
complex V assembly factor, and (3) to test the liver ISR as a mechanism of liver resiliency by using the
acetaminophen overdose as a model for drug-induced liver injury. Completion of the proposed studies will
generate a new paradigm for the mechanisms of the liver ISR and OPA1 function, and provide scientific basis
for a new therapeutic strategy to decrease liver diseases.

## Key facts

- **NIH application ID:** 10909565
- **Project number:** 1R56DK136753-01
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Weiqin Chen
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $438,900
- **Award type:** 1
- **Project period:** 2023-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909565

## Citation

> US National Institutes of Health, RePORTER application 10909565, Mitochondrial stress in liver function and dysfunction (1R56DK136753-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10909565. Licensed CC0.

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