期刊
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
卷 306, 期 4, 页码 G265-G277出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00278.2013
关键词
liver; mitochondria; alcohol; cyclophilin D; permeability transition pore
资金
- National Institutes of Health [AA-015172, AA-018841, NS-071168]
- Research Supplement to Promote Diversity in Health-Related Research linked to the parent grant [AA-015172]
Chronic ethanol consumption increases sensitivity of the mitochondrial permeability transition (MPT) pore induction in liver. Ca2+ promotes MPT pore opening, and genetic ablation of cyclophilin D (CypD) increases the Ca2+ threshold for the MPT. We used wild- type (WT) and CypD-null (CypD(-/-)) mice fed a control or an ethanol-containing diet to investigate the role of the MPT in ethanol-mediated liver injury. Ca2+ -mediated induction of the MPT and mitochondrial respiration were measured in isolated liver mitochondria. Steatosis was present in WT and CypD(-/-) mice fed ethanol and accompanied by increased terminal deoxynucleotidyl transferase dUTP-mediated nick-end label-positive nuclei. Autophagy was increased in ethanol-fed WT mice compared with ethanol-fed CypD(-/-) mice, as reflected by an increase in the ratio of microtubule protein 1 light chain 3B II to microtubule protein 1 light chain 3B I. Higher levels of p62 were measured in CypD(-/-) than WT mice. Ethanol decreased mitochondrial respiratory control ratios and select complex activities in WT and CypD(-/-) mice. Ethanol also increased CypD protein in liver of WT mice. Mitochondria from control-and ethanol-fed WT mice were more sensitive to Ca2+ -mediated MPT pore induction than mitochondria from their CypD(-/-) counterparts. Mitochondria from ethanol-fed CypD(-/-) mice were also more sensitive to Ca2+ -induced swelling than mitochondria from control-fed CypD(-/-) mice but were less sensitive than mitochondria from ethanol-fed WT mice. In summary, CypD deficiency was associated with impaired autophagy and did not prevent ethanol-mediated steatosis. Furthermore, increased MPT sensitivity was observed in mitochondria from ethanol-fed WT and CypD(-/-) mice. We conclude that chronic ethanol consumption likely lowers the threshold for CypD-regulated and -independent characteristics of the ethanol-mediated MPT pore in liver mitochondria.
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