ReviewAlcoholism, clinical and experimental research2018
A Unifying Hypothesis Linking Hepatic Adaptations for Ethanol Metabolism to the Proinflammatory and Profibrotic Events of Alcoholic Liver Disease.
Review in Alcoholism, clinical and experimental research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 54 citations in OpenAlex.
- Zonal hepatocellular responses to acute ethanol consumption: impacts on mitochondrial function and liver metabolism.Toxicological sciences : an official journal of the Society of Toxicology · 2026Article
- Mitochondrial Calcium Signaling in Hepatocyte Health and Disease.Cold Spring Harbor perspectives in biology · 2026Review
- Role of Acetaldehyde and Dysregulated Mitophagic Lysosomal Processing in Chronic-Binge Ethanol-Induced Liver Injury.International journal of molecular sciences · 2025Article
- Comprehensive review on alcohol-induced protein modifications in hepatic mitochondrial membranes and their functional implications.Molecular biology reports · 2025Review
- Mitophagy in relation to chronic inflammation/ROS in aging.Molecular and cellular biochemistry · 2025Review
- Exercise regulates mitophagy to alleviate parkinsonian neurodegeneration.Frontiers in aging neuroscience · 2025Review
- Formoterol promotes mitochondrial biogenesis, improves liver regeneration, and suppresses liver injury and inflammation after liver resection in mice with endotoxemia.International journal of physiology, pathophysiology and pharmacology · 2025Article
- Promoting Alzheimer's disease research and therapy with stem cell technology.Stem cell research & therapy · 2024Review
- Important Role of Mitochondrial Dysfunction in Immune Triggering and Inflammatory Response in Rheumatoid Arthritis.Journal of inflammation research · 2024Review
- Phosphoglycerate mutase 5 aggravates alcoholic liver disease through disrupting VDAC-1-dependent mitochondrial integrity.International journal of medical sciences · 2024Article
- Mitophagy in fibrotic diseases: molecular mechanisms and therapeutic applications.Frontiers in physiology · 2024Review
- Walnut (Nutrients · 2023Article
- Mitochondrial depolarization after acute ethanol treatment drives mitophagy in living mice.Autophagy · 2022Article
- Mechanism Analysis of Metabolic Fatty Liver on Largemouth Bass (Metabolites · 2022Article
- Advancements in the Alcohol-Associated Liver Disease Model.Biomolecules · 2022Review
- Hepatocellular Carcinoma: Understanding the Inflammatory Implications of the Microbiome.International journal of molecular sciences · 2022Review
- Production of Bioactive Substances to Alleviates Hangover and Ethanol-Induced Liver Damage through Fermentation ofMolecules (Basel, Switzerland) · 2022Article
- Quercetin Protects Ethanol-Induced Hepatocyte Pyroptosis via Scavenging Mitochondrial ROS and Promoting PGC-1Oxidative medicine and cellular longevity · 2022Article
- Environmental toxicant-induced maladaptive mitochondrial changes: A potential unifying mechanism in fatty liver disease?Acta pharmaceutica Sinica. B · 2021Review
- Metabolic implications of non-electrogenic ATP/ADP exchange in cancer cells: A mechanistic basis for the Warburg effect.Biochimica et biophysica acta. Bioenergetics · 2021Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The pathogenesis of alcoholic liver disease (ALD) remains poorly understood but is likely a multihit pathophysiological process. Here, we propose a hypothesis of how early mitochondrial adaptations for alcohol metabolism lead to ALD pathogenesis. Acutely, ethanol (EtOH) feeding causes a near doubling of hepatic EtOH metabolism and oxygen consumption within 2 to 3 hours. This swift increase in alcohol metabolism (SIAM) is an adaptive response to hasten metabolic elimination of both EtOH and its more toxic metabolite, acetaldehyde (AcAld). In association with SIAM, EtOH causes widespread hepatic mitochondrial depolarization (mtDepo), which stimulates oxygen consumption. In parallel, voltage-dependent anion channels (VDAC) in the mitochondrial outer membrane close. Together, VDAC closure and respiratory stimulation promote selective and more rapid oxidation of EtOH first to AcAld in the cytosol and then to nontoxic acetate in mitochondria, since membrane-permeant AcAld does not require VDAC to enter mitochondria. VDAC closure also inhibits mitochondrial fatty acid oxidation and ATP release, promoting steatosis and a decrease in cytosolic ATP. After acute EtOH, these changes revert as EtOH is eliminated with little hepatocellular cytolethality. mtDepo also stimulates mitochondrial autophagy (mitophagy). After chronic high EtOH exposure, the capacity to process depolarized mitochondria by mitophagy becomes compromised, leading to intra- and extracellular release of damaged mitochondria, mitophagosomes, and/or autolysosomes containing mitochondrial damage-associated molecular pattern (mtDAMP) molecules. mtDAMPs cause inflammasome activation and promote inflammatory and profibrogenic responses, causing hepatitis and fibrosis. We propose that persistence of mitochondrial responses to EtOH metabolism becomes a tipping point, which links initial adaptive EtOH metabolism to maladaptive changes initiating onset and progression of ALD.
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