{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T20:36:57Z","timestamp":1776371817273,"version":"3.51.2"},"reference-count":82,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T00:00:00Z","timestamp":1764374400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["R01 AA025379"],"award-info":[{"award-number":["R01 AA025379"]}]},{"name":"National Institute of Health","award":["P20 GM130457"],"award-info":[{"award-number":["P20 GM130457"]}]},{"name":"National Institute of Health","award":["P30 CA138313"],"award-info":[{"award-number":["P30 CA138313"]}]},{"name":"National Institute of Health","award":["P30 DK123704"],"award-info":[{"award-number":["P30 DK123704"]}]},{"name":"National Institute of Health","award":["P20 GM103542"],"award-info":[{"award-number":["P20 GM103542"]}]},{"name":"National Institute of Health","award":["S10 OD018113"],"award-info":[{"award-number":["S10 OD018113"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms262311608","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T08:13:49Z","timestamp":1764576829000},"page":"11608","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Role of Acetaldehyde and Dysregulated Mitophagic Lysosomal Processing in Chronic-Binge Ethanol-Induced Liver Injury"],"prefix":"10.3390","volume":"26","author":[{"given":"Devadoss J.","family":"Samuvel","sequence":"first","affiliation":[{"name":"Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4710-4379","authenticated-orcid":false,"given":"Emory","family":"Foerster","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amir K.","family":"Richardson","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9471-1916","authenticated-orcid":false,"given":"Patrick M.","family":"Wooster","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John J.","family":"Lemasters","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA"},{"name":"Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1146\/annurev-pathmechdis-031521-030435","article-title":"Recent Advances in Understanding of Pathogenesis of Alcohol-Associated Liver Disease","volume":"18","author":"Wu","year":"2023","journal-title":"Annu. 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