Chronic ethanol consumption enhances sensitivity to Ca -mediated opening of the mitochondrial permeability transition pore and increases cyclophilin D in liver

King AL, Swain TM, Dickinson DA, Lesort MJ, Bailey SM. Chronic ethanol consumption enhances sensitivity to Ca -mediated opening of the mitochondrial permeability transition pore and increases cyclophilin D in liver. Am J Physiol Gastrointest Liver Physiol 299: G954– G966, 2010. First published July 22, 2010; doi:10.1152/ajpgi.00246.2010.— Chronic ethanol consumption increases mitochondrial oxidative stress and sensitivity to form the mitochondrial permeability transition pore (MPTP). The mechanism responsible for increased MPTP sensitivity in ethanol-exposed mitochondria and its relation to mitochondrial Ca handling is unknown. Herein, we investigated whether increased sensitivity to MPTP induction in liver mitochondria from ethanol-fed rats compared with controls is related to an ethanoldependent change in mitochondrial Ca accumulation. Liver mitochondria were isolated from control and ethanol-fed rats, and Ca mediated induction of the MPTP and mitochondrial Ca retention capacity were measured. Levels of proposed MPTP proteins as well as select proand antiapoptotic proteins were measured along with gene expression. We observed increased steatosis and TUNEL-stained nuclei in liver of ethanol-fed rats compared with controls. Liver mitochondria from ethanol-fed rats had increased levels of proapoptotic Bax protein and reduced Ca retention capacity compared with control mitochondria. We observed increased cyclophilin D (Cyp D) gene expression in liver and protein in mitochondria from ethanol-fed animals compared with controls, whereas there was no change in the adenine nucleotide translocase and voltage-dependent anion channel. Together, these results suggest that enhanced sensitivity to Ca mediated MPTP induction may be due, in part, to higher Cyp D levels in liver mitochondria from ethanol-fed rats. Therefore, therapeutic strategies aimed at normalizing Cyp D levels may be beneficial in preventing ethanol-dependent mitochondrial dysfunction and liver injury.