Role of Ethanol Metabolism in Intravital Hepatic Mitochondrial Depolarization

Abstract

Mitochondrial dysfunction plays an important role in alcoholic liver disease. This study investigated the relation between alcohol metabolism and mitochondrial depolarization in vivo. Mitochondrial polarization and cell death were assessed in living mice by intravital multiphoton microscopy of rhodamine 123 and propidium iodide, respectively. Intravital mitochondrial depolarization occurred as early as 1 h after acute ethanol treatment (6 g/kg, i.g.). After 6 h, 94% hepatocytes contained depolarized mitochondria, but cell death was barely detectable. Similar intravital depolarization occurred in alcohol dehydrogenase (ADH)‐positive deer mice. By contrast in ADH‐negative deer mice, mitochondrial depolarization only occurred in 26% of hepatocytes. Ethanol‐induced mitochondrial depolarization was blunted by ~25% in livers of CYP2E1 deficient mice and after treatment of wildtype mice with a cytochrome P450 inhibitor aminobenzotriazole. Disulfiram, an aldehyde dehydrogenase inhibitor, accelerated ethanol‐induced mitochondrial depolarization, and acetaldehyde infusion into the liver alone caused mitochondrial depolarization. Together, these data suggest that acetaldehyde formation mediates, at least in part, ethanol‐induced mitochondrial depolarization in vivo and that ethanol metabolism by ADH plays a larger role than CYP2E1 in producing this effect (NIAAA).