Perturbation of mitochondrial dynamics in Alcoholic Liver Disease.

In Europe alcohol consumption causes 6.5% of deaths and Alcoholic Liver Disease (ALD) is the predominant cause of liver disease[1]. In the pathogenesis of ALD the involvement of mitochondria is well established[2, 3], morphological alterations (megamitochondria) in the liver biopsies of patients are recognised as hallmarks of ALD[4]. However, the impact of alcohol on mitochondrial dynamics and mitochondria-shaping proteins (MSP) remains unknown. The effect of alcohol was investigated in vitro (hepatoma cells), ex vivo (human liver slices) and in 55 patients with ALD. The analysis by confocal/electron microscopy revealed an initial mitochondrial hyper-fragmentation induced by short-term ethanol treatment, preceding cell injury or mitochondrial dysfunction; while megamitochondria developed as a consequence of longer exposure. These structural modifications were associated with changes in the MSP regulating fragmentation but not fusion (gene/protein expression), in particular in Dynamin related protein-1 (Drp-1) and its receptors MiD51 and Mff. When Drp-1 was inactivated, the cells shown abrogation of ethanol-induced hyper-fragmentation and increased megamitochondria formation, suggesting that both phenomena are induced by alcohol via Drp-1. The pivotal role of Drp-1 in ALD was confirmed in liver biopsies of patients with alcoholic hepatitis, opening new perspectives in the development of therapies aimed to modulate its activity.