# Mitochondrial depolarization, mitophagy, and mitochondrial DAMPs in ALD

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2022 · $336,375

## Abstract

Alcoholic liver disease (ALD) accounts for ~50% of deaths due to cirrhosis and ~30% of all liver-related
deaths in the US. How ethanol damages the liver remains poorly understood, and therapies are lacking or
unproven. Our goal is to understand the pathogenesis of ALD. We observed widespread, reversible hepatic
mitochondrial depolarization (mtDepo), increased mitophagic burden and elevated serum mitochondrial DNA
(mtDNA) in mice after ethanol treatment. We propose to test the novel hypothesis that ethanol metabolism
induces mtDepo, which in turn stimulates mitophagy. Markedly increased mitophagic burden
overwhelms the capacity of lysosomes to process autophagosomes, particularly when processing of
depolarized mitochondria into mitophagosomes and then into lysosomes is compromised after
chronic ethanol exposure, leading to extracellular release of damaged mitochondria, mitophagosomes
and/or autolysosomes containing mitochondrial damage-associated molecular pattern (mtDAMP)
molecules to cause a profibrotic inflammatory response and liver injury. In Specific Aim 1 using
intravital multiphoton microscopy, we will explore if mtDepo occurs in living mice after chronic ethanol and is
exacerbated by superimposed binge drinking and in an unique fibrosis-inducing ethanol/cholesterol model we
developed. We will determine the relation of mtDepo to hepatic injury, inflammation and fibrosis. We will also
explore if inhibition of acetaldehyde (AcAld) formation by alcohol dehydrogenase and CYP2E1 deficiency,
accelerated AcAld oxidation by Alda-1, and FK506 (blocker of depolarization) decrease mtDepo and liver
injury/inflammation/fibrosis after chronic ethanol. In Aim 2, we will determine the relation of mtDepo to
mitophagy. Using genetic and pharmacological interventions in combination with intravital and electron
microscopy and analyses of molecular indicators of mitophagic flux, we will elucidate if ethanol-induced
mtDepo initiates mitophagy or if mitophagy causes mtDepo. We will determine if mitophagy/mitophagosome
processing is blunted by chronic, chronic plus cholesterol and chronic plus binge ethanol and further explore if
inhibition of autophagic processing exacerbates liver injury/inflammation/fibrosis after chronic ethanol. In Aim
3, we will characterize how mtDepo and compromised mitophagy/processing contribute to mtDAMP release
after ethanol. We will characterize release into serum of mtDAMPs after acute ethanol and chronic, chronic
plus cholesterol and chronic plus binge ethanol to determine the relationship of mtDAMP release to liver
injury/inflammation/fibrosis. We will also determine how up and down-modulation of mtDepo, mitophagy and
processing of mitophagosomes alters mtDAMP release after ethanol. This study will elucidate a novel link
between early mitochondrial changes associated with ethanol metabolism and the later development of liver
injury/inflammation/fibrosis and thus fill a critical gap in understanding ALD pathogenesis. This study sho...

## Key facts

- **NIH application ID:** 10398017
- **Project number:** 5R01AA025379-05
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** John J Lemasters
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $336,375
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10398017

## Citation

> US National Institutes of Health, RePORTER application 10398017, Mitochondrial depolarization, mitophagy, and mitochondrial DAMPs in ALD (5R01AA025379-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10398017. Licensed CC0.

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