Chronic ethanol consumption enhances sensitivity to Ca²⁺-mediated opening of the mitochondrial permeability transition pore and increases cyclophilin D in liver

Abstract

King AL, Swain TM, Dickinson DA, Lesort MJ, Bailey SM. Chronic ethanol consumption enhances sensitivity to Ca 2ϩ -mediated opening of the mitochondrial permeability transition pore and increases cyclophilin D in liver.

Involvement of the mitochondrial permeability transition pore in chronic ethanol-mediated liver injury in mice

“…Previously, we reported that chronic ethanol consumption increased CypD at gene and protein levels in liver, whereas other proposed MPT pore components, including the adenine nucleotide translocator (ANT), remained unchanged (47). We also observed that chronic ethanol consumption enhanced sensitivity to Ca 2ϩ -dependent opening of the MPT pore in isolated rat liver mitochondria (47). These data suggest that increased CypD levels may predispose liver mitochondria to undergo MPT pore formation and opening in response to chronic ethanol consumption.…”

“…These findings suggest that CypD-dependent regulation of the MPT pore may play a crucial role in cellular responses to stresses relevant to human disease, especially diseases induced by Ca 2ϩ overload and oxidative stress. Previously, we reported that chronic ethanol consumption increased CypD at gene and protein levels in liver, whereas other proposed MPT pore components, including the adenine nucleotide translocator (ANT), remained unchanged (47). We also observed that chronic ethanol consumption enhanced sensitivity to Ca 2ϩ -dependent opening of the MPT pore in isolated rat liver mitochondria (47).…”

“…Steatosis (percentage of hepatocytes containing lipid droplets) was scored by a pathologist blinded to the experimental design. Terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling (TUNEL) was performed in liver sections to determine whether cell death was increased by chronic ethanol consumption (47). Briefly, deparaffinized and rehydrated liver sections were subjected to antigen retrieval by incubation in 0.1 M citrate buffer (pH 6.0) followed by blocking for 1 h at room temperature with 0.1 M Tris·HCl (pH 7.5) containing 5% (wt/vol) BSA.…”

Ethanol-Induced Mitochondrial Induction of Cell Death-Pathways Explored

“…Chronic EtOH exposure in rats leads to sustained Ca 2+ elevation that triggers MPTP opening. MPTP opening leads to Ca 2+ overload in the mitochondria and results in mitochondrial swelling a phenomenon observed in EtOH fed rats but not in control rats (45). Cells at basal metabolic rate tightly regulate free Ca 2+ in the range of 100 to 200 nM in both cytosol and mitochondria through NCX (Na + /Ca 2+ exchanger), PMCA (Plasma membrane Ca 2+ -ATPase) and SERCA (Sarcoendoplasmic reticulum Ca 2+ -ATPase) pumps.…”

“…ER-mitochondria link and the mitochondrial Ca 2+ ([Ca 2+ ] m ) uptake through uniporter is known to promote [Ca 2+ ] m overload which subsequently leads to mitochondrial depolarization and increased mROS production (10,28,35,36). The aberrant Ca 2+ homeostasis has been linked with ALD (37,38). Despite the vast knowledge, the actual intricacies on the mechanism of Ca 2+ induced mitochondrial dysfunction remain largely unexplored.…”