# Mechanisms of mitochondrial dynamics, quality control and mtDNA-mediated inflammation in alcohol-associated liver disease

> **NIH NIH R01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2024 · $386,196

## Abstract

Project Summary/Abstract
Despite recent progress on understanding the mechanisms of alcohol-associated liver disease (ALD), no
successful treatment for ALD is available. Alcohol metabolism in the liver leads to decreased levels of
nicotinamide adenine dinucleotide (NAD+) and increased NADH/ NAD+ ratio resulting in impaired alcohol
metabolism, mitochondrial dysfunction and oxidative stress. The widely accepted notion that alcohol induces
mitochondrial dysfunction is largely derived from the results on chronic alcohol-fed rats. However, we and
others recently demonstrated that chronic alcohol-fed mice have increased mitochondrial respiration with
increased number of megamitochondria in the liver. Increased mitochondrial respiration regenerates NAD+,
which can be further used for alcohol metabolism via alcohol dehydrogenase and aldehyde dehydrogenase 2,
suggesting alcohol induces an adaptive response to facilitate alcohol metabolism by increasing mitochondria
respiration. It has long been known that accumulation of hepatic megamitochondria is associated with better
outcomes in human ALD although the exact role and mechanisms of megamitochondria in the pathogenesis of
ALD are unknown. We recently showed that alcohol decreases mitochondria fission protein dynamin-related
protein 1 (DRP1) (gene name DNM1L) in mouse livers and human alcohol-associated hepatitis resulting in
increased megamitochondria formation. We further demonstrated that chronically accumulated
megamitochondria are maladaptive resulting in impaired NAD+ regeneration, increased mtDNA release and
cGAS-STING-mediated innate immune response in alcohol-fed mice. Liver-specific Dnm1l knockout (L-Dnm1l
KO) mice developed spontaneous liver tumors and was further exacerbated by alcohol feeding. Deletion of
mitochondrial fusion protein (mitofusin 1 and 2) to regain liver mitochondrial “stasis” remarkably abolished
cGAS-STING-mediated innate immune response and tumorigenesis in L-Dnm1l KO mice. The goal of this
proposal is to understand the mechanisms for how megamitochondria are maladaptive to promote mtDNA
release and how cGAS-STING pathway contributes to the pathogenesis of ALD and liver cancer. The central
hypothesis is that chronically accumulated megamitochondria impair mitophagy and increase BAX/BAK pore
formation to promote mtDNA release and cGAS-STING-mediated innate immune response resulting in alcohol-
induced liver injury and tumorigenesis, all of which can be restrained by re-establishing hepatic mitochondrial
stasis. The study will identify novel mechanisms of mitochondrial dynamics and homeostasis in regulating
hepatic inflammation and liver tumorigenesis in ALD, which may help develop new therapeutic options by
targeting mitochondria for ALD.

## Key facts

- **NIH application ID:** 10978419
- **Project number:** 1R01AA031230-01A1
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Wen-Xing Ding
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $386,196
- **Award type:** 1
- **Project period:** 2024-08-20 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978419

## Citation

> US National Institutes of Health, RePORTER application 10978419, Mechanisms of mitochondrial dynamics, quality control and mtDNA-mediated inflammation in alcohol-associated liver disease (1R01AA031230-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10978419. Licensed CC0.

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