Mitochondrial Ca2+ influx and efflux rates in guinea pig cardiac mitochondria:Low and high affinity effects of cyclosporine A

被引:51
作者
Wei, An-Chi [2 ]
Liu, Ting [1 ]
Cortassa, Sonia [1 ,2 ]
Winslow, Raimond L. [2 ]
O'Rourke, Brian [1 ]
机构
[1] Johns Hopkins Univ, Inst Mol Cardiobiol, Dept Med, Baltimore, MD 21205 USA
[2] Johns Hopkins Univ, Dept Biomed Engn, Inst Computat Med, Baltimore, MD 21205 USA
来源
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH | 2011年 / 1813卷 / 07期
关键词
Mitochondrial Na+/Ca2+ exchanger; Permeability transition pore; Mitochondrial calcium uniporter; Oxidative phosphorylation; Bioenergetics; Calcium transport; PERMEABILITY TRANSITION PORE; ISCHEMIA-REPERFUSION INJURY; CALCIUM-TRANSPORT; HEART-MITOCHONDRIA; LIVER-MITOCHONDRIA; OXIDATIVE-PHOSPHORYLATION; NA+/CA2+ EXCHANGE; CELL-DEATH; INHIBITION; MYOCYTES;
D O I
10.1016/j.bbamcr.2011.02.012
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Ca2+ plays a central role in energy supply and demand matching in cardiomyocytes by transmitting changes in excitation-contraction coupling to mitochondrial oxidative phosphorylation. Matrix Ca2+ is controlled primarily by the mitochondrial Ca2+ uniporter and the mitochondrial Na+/Ca2+ exchanger, influencing NADH production through Ca2+-sensitive dehydrogenases in the Krebs cycle. In addition to the well-accepted role of the Ca2+-triggered mitochondrial permeability transition pore in cell death, it has been proposed that the permeability transition pore might also contribute to physiological mitochondrial Ca2+ release. Here we selectively measure Ca2+ influx rate through the mitochondrial Ca2+ uniporter and Ca2+ efflux rates through Na+-dependent and Na+-independent pathways in isolated guinea pig heart mitochondria in the presence or absence of inhibitors of mitochondrial Na+/Ca2+ exchanger (CGP 37157) or the permeability transition pore (cyclosporine A). cyclosporine A suppressed the negative bioenergetic consequences (Delta Psi(m) loss, Ca2+ release, NADH oxidation, swelling) of high extramitochondrial Ca2+ additions, allowing mitochondria to tolerate total mitochondrial Ca2+ loads of >400 nmol/mg protein. For Ca2+ pulses up to 15 mu M, Na+-independent Ca2+ efflux through the permeability transition pore accounted for similar to 5% of the total Ca2+ efflux rate compared to that mediated by the mitochondrial Na+/Ca2+ exchanger (in 5 mM Na+). Unexpectedly, we also observed that cyclosporine A inhibited mitochondrial Na+/Ca2+ exchanger-mediated Ca2+ efflux at higher concentrations (IC50 = 2 mu M) than those required to inhibit the permeability transition pore, with a maximal inhibition of similar to 40% at 10 mu M cyclosporine A, while having no effect on the mitochondrial Ca2+ uniporter. The results suggest a possible alternative mechanism by which cyclosporine A could affect mitochondrial load in cardiomyocytes, potentially explaining the paradoxical toxic effects of cyclosporine A at high concentrations. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection. (C) 2011 Elsevier B.V. All rights reserved.
引用
收藏
页码:1373 / 1381
页数:9
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