Role of Acetaldehyde and Dysregulated Mitophagic Lysosomal Processing in Chronic-Binge Ethanol-Induced Liver Injury
Year: 2025
Type: article
Abstract: Chronic binge drinking is common among patients with alcohol-associated steatohepatitis. Therefore, we tested the hypothesis that chronic binge ethanol exposure disrupts mitophagic processing and stimulates release of mitochondrial damage-associated molecular patterns (mtDAMPs), thereby promoting hepatic inflammation and fibrosis after chronic binge ethanol (CBE) exposure in mice using the National Institute of Alcohol Abuse and Alcoholism model. After CBE, hepatic steatosis, liver injury, inflammation, and hepatic stellate cell (HSC) activation occurred. Alda-1, an aldehyde dehydrogenase-2 activator, attenuated these changes. After CBE, mitochondrial depolarization (mtDepo) occurred in ~85% hepatocytes, and mitophagy-associated proteins increased, which Alda-1 blunted. By contrast, transcription factor-EB (master regulator of lysosomal biogenesis) and lysosomal markers decreased, indicating disrupted lysosomal processing. After mitophagy, mitochondrial biogenesis (MB) restores mitochondrial mass and function. After CBE, peroxisome proliferator-activated receptor gamma coactivator-1 alpha (MB regulator), mitochondrial transcription factor-A, oxidative phosphorylation proteins, and fatty acid oxidation all decreased, which Alda-1 largely restored. After CBE, serum mtDAMPs (mitochondrial DNA and cytochrome c) increased 3- to 10-fold. In vitro, mitochondrial DNA stimulated macrophage and HSC activation, which was prevented by toll-like receptor-9 inhibition. In conclusion, CBE increases mtDepo in an acetaldehyde-dependent fashion, leading to mitophagic overburden, disruption of mitochondrial homeostasis, mtDAMP release, and ultimately development of liver inflammation and injury.
Authors: Devadoss J. Samuvel, Emory Foerster, Li Li, Amir K. Richardson, Patrick M. Wooster, John J. Lemasters, Zhi Zhong
Institution: Medical University of South Carolina
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,499
Funders: Medical University of South Carolina, University of South Carolina, National Institutes of Health, Centers for Disease Control and Prevention, Hollings Cancer Center, Medical University of South Carolina, National Institute on Alcohol Abuse and Alcoholism, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1410469566, G1436149861, Mechanisms of Mitochondrial Iron Uptake: New Therapeutic Targets in Hepatotoxicity, G2478139894, G3259573665, G4223979924, G4424592439, G4796340452, G732836964, G8442482983, COBRE in Digestive and Liver Disease, Medical University of South Carolina - Cancer Center Support Grant
OpenAlex ID: W4416844591
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