Korge P, Langer G A
Department of Physiology, University of California Los Angeles School of Medicine, Los Angeles, California 90095-1760, USA.
Am J Physiol. 1998 Jun;274(6):H2085-93. doi: 10.1152/ajpheart.1998.274.6.H2085.
The purpose of this study was to determine mitochondrial Ca2+ accumulation and its possible role in initiation of mitochondrial permeability transition (MPT) and sarcolemmal damage in Ca2+-overloaded cardiomyocytes. Cellular Ca2+ overload, generated secondary to ouabain or p-chloromercuribenzoate-stimulated cell Na+ concentration increase, induced Ca2+ accumulation in mitochondria (approximately 3/4 of total net uptake) as identified by kinetic analysis and verified by use of mitochondrial inhibition. Mitochondrial Ca2+ uptake was followed by a rapid Ca2+ efflux ( approximately 1 mmol . kg dry wt-1 . min-1) that can be best explained by efflux via Ca2+-dependent nonspecific pores. Cell ATP concentration was stable during mitochondrial Ca2+ uptake and decreased in parallel with Ca2+ efflux. In addition, sarcolemmal damage was not related to the increase in mitochondrial Ca2+ concentration per se, but rather connected with the extent of Ca2+ efflux from the mitochondria. A decrease in the rate of this Ca2+ efflux, indicating also a decrease in a subpopulation of mitochondria with open pores, was followed by decreased sarcolemmal damage. Both dithiothreitol and cyclosporin A decreased rapid Ca2+ efflux and inhibited sarcolemmal damage, implicating MPT as an important component in the mechanism of sarcolemmal damage.
本研究的目的是确定线粒体Ca2+蓄积及其在Ca2+过载心肌细胞中线粒体通透性转换（MPT）起始和肌膜损伤中的可能作用。哇巴因或对氯汞苯甲酸刺激细胞Na+浓度升高继发产生的细胞Ca2+过载，诱导线粒体Ca2+蓄积（约占总净摄取量的3/4），这通过动力学分析得以确定，并通过使用线粒体抑制剂得到验证。线粒体Ca2+摄取之后是快速的Ca2+外流（约1 mmol·kg干重-1·min-1），这可以通过依赖Ca2+的非特异性孔道外流得到最好的解释。细胞ATP浓度在线粒体Ca2+摄取期间保持稳定，并与Ca2+外流平行下降。此外，肌膜损伤与线粒体Ca2+浓度本身的增加无关，而是与线粒体Ca2+外流的程度有关。这种Ca2+外流速率的降低，也表明具有开放孔道的线粒体亚群减少，随后肌膜损伤减轻。二硫苏糖醇和环孢素A均降低了快速Ca2+外流并抑制了肌膜损伤，这表明MPT是肌膜损伤机制中的一个重要组成部分。
