Perturbations in Mitochondrial Dynamics Are Closely Involved in the Progression of Alcoholic Liver Disease. (25th February 2020)

• Record Type: Journal Article
• Authors: Palma, Elena; Riva, Antonio; Moreno, Christophe; Odena, Gemma; Mudan, Satvinder; Manyakin, Nikolai; Miquel, Rosa; Degré, Delphine; Trepo, Eric; Sancho‐Bru, Pau; Altamirano, Jose; Caballeria, Juan; Zamalloa, Ane; Menon, Krishna; Heaton, Nigel; Williams, Roger; Bataller, Ramon; Chokshi, Shilpa
• Is Part Of: Alcoholism. Volume 44:Number 4(2020)
• Page Start: 856
• Page End: 865
• Publication Date: 2020-02-25
• Subjects: Alcoholic Liver Disease -- Mitochondrial Fragmentation -- Dynamin‐1‐Like Protein -- Precision‐Cut Liver Slices -- Alcoholic Hepatitis; Alcoholism -- Periodicals; Alcoholism -- Periodicals; Alcoolisme; Electronic journals; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.861005
• DOI: 10.1111/acer.14299
• Languages: English
• ISSNs: 0145-6008

Abstract

Abstract : Background: Mitochondria play a fundamental role in the pathogenesis of alcoholic liver disease (ALD). The preservation of functional mitochondria during toxic alcohol insults is essential for cell survival and is maintained by key processes known as mitochondrial dynamics, including fragmentation and fusion, which are regulated by mitochondria‐shaping proteins (MSP). We have shown mitochondrial dynamics to be distorted by alcohol in cellular and animal models, but the effect in humans remains unknown. Methods: Hepatic gene expression of the main MSP involved in the mitochondrial fusion and fragmentation pathways was evaluated in patients with alcoholic hepatitis (AH) by DNA microarray ( n = 15) and Reverse Transcription Polymerase Chain Reaction ( n = 32). The activation of dynamin‐1‐like protein (Drp1) was also investigated in mitochondria isolated from liver biopsies of ALD patients ( n = 8). The effects of alcohol on mitochondrial dynamics and on MSP protein expression were studied in human precision‐cut liver slices (PCLS) exposed for 24 hours to increasing doses of ethanol (EtOH; 50 to 250 mM). Results: A profound hyperactivation of the fragmentation pathway was observed in AH patients, with a significant increase in the expression of Drp1 and its adapters/receptors. The translocation of Drp1 to the mitochondria was also induced in patients with severe ALD and was affected in the PCLS with short‐term exposure to EtOH but only mildly. The fusion pathway was not altered in ALD, and this was confirmed in the PCLS model. Conclusions: The present study reveals the role of mitochondrial dynamics in human ALD, confirming our previous observations in animal and cell culture models of ALD. Taken together, we show that alcohol has a significant impact on the fragmentation pathway, and we confirm Drp1 as a potential therapeutic target in severe ALD. Abstract : Despite the global burden of Alcoholic Liver Disease (ALD), this life‐threatening disorder remains a 'treatment enigma' and the development of novel therapies is crucial. The present study reveals the role of mitochondrial dynamics in ALD and identifies Dynamin‐1‐like protein (Drp1) as the main mitochondria‐shaping protein affected in patients. These findings, combined with our previous observations in animal and cell models (Palma et al., Am J Pathol. 2019) suggest Drp1 pathway as a potential druggable target to reduce alcohol‐related liver damage.