Chronic ethanol consumption enhances sensitivity to Ca(2+)-mediated opening of the mitochondrial permeability transition pore and increases cyclophilin D in liver.
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(2+) 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 ethanol-dependent change in mitochondrial Ca(2+) accumulation. Liver mitochondria were isolated from control and ethanol-fed rats, and Ca(2+)-mediated induction of the MPTP and mitochondrial Ca(2+) retention capacity were measured. Levels of proposed MPTP proteins as well as select pro- and 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(2+) 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(2+)-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.
King
Adrienne L
AL
Dept. of Environmental Health Sciences, Center for Free Radical Biology, Univ. of Alabama at Birmingham, AL 35294, USA.
Swain
Telisha M
TM
Dickinson
Dale A
DA
Lesort
Mathieu J
MJ
Bailey
Shannon M
SM
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism*; D000431:Ethanol / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D000083162:Mitochondrial Permeability Transition Pore; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley
D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D000431:Ethanol; D021983:Cyclophilins; D002118:Calcium