Elena Palma1,2, Antonio Riva1,2, Christophe Moreno3,4, Gemma Odena5, Satvinder Mudan6, Nikolai Manyakin6, Rosa Miquel7, Delphine Degré3,4, Eric Trepo3,4, Pau Sancho-Bru8,9, Jose Altamirano8, Juan Caballeria8,9,10, Ane Zamalloa7, Krishna Menon7, Nigel Heaton7, Roger Williams1,2, Ramon Bataller5, Shilpa Chokshi1,2. 1. From the, Institute of Hepatology, (EP, AR, RW, SC), Foundation for Liver Research, London, UK. 2. Faculty of Life Sciences and Medicine, (EP, AR, RW, SC), King's College London, London, UK. 3. Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, (CM, DD, ET), CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. 4. Laboratory of Experimental Gastroenterology, (CM, DD, ET), Université Libre de Bruxelles, Brussels, Belgium. 5. Division of Gastroenterology and Hepatology, (GO, RB), Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 6. The London Clinic, (SM, NM), London, UK. 7. Institute of Liver Studies, (RM, AZ, KM, NH), King's College London, London, UK. 8. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), (PS-B, JA, JC), Barcelona, Spain. 9. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), (PS-B, JC), Barcelona, Spain. 10. Liver Unit, (JC), Hospital Clínic, Barcelona, Spain.
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.
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.
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