Griffiths Elinor J
Department of Biochemistry, School of Medical Sciences, and Bristol Heart Institute, University of Bristol, Bristol, UK.
J Mol Cell Cardiol. 2009 Jun;46(6):789-803. doi: 10.1016/j.yjmcc.2009.03.001. Epub 2009 Mar 12.
That intramitochondrial free calcium (Ca(2+)) plays various critical roles in both normal physiological and pathological conditions in the heart is now well-accepted, and evidenced by the interest and work in this area of the last two decades. However, controversies remain; such as the existence of beat-to-beat mitochondrial Ca(2+) transients, role of Ca(2+) in modulating whole-cell Ca(2+) signalling, whether or not Ca(2+) is critical for increases in ATP supply upon increased demand, and its role in cell death by both necrosis and apoptosis, especially in formation of the mitochondrial permeability transition pore and in ischaemic preconditioning. Neither is there a consensus as to whether inhibiting the Ca(2+) influx or efflux pathways--the Ca(2+) uniporter (MCU) and Na(+)/Ca(2+)-excahnger (mNCX), respectively--is cardioprotective, largely due to lack of specific inhibitors of these transporters. Ruthenium red, Ru360, clonazepam and CGP37157 are all very effective in isolated mitochondria, but reports of their effectiveness in whole cell and heart studies vary considerably, which partly accounts for the lack of a consensus on protective effects. The purification and cloning of the transporters, and development of more specific inhibitors, would produce a step-change in our understanding of the role of these apparently critical but still elusive proteins. However, developments in fluorescent indicators, proteins and imaging technology have meant that Ca(2+) can now be measured reasonably specifically in intact cells and hearts, and interactions of the mitochondrial Ca(2+) transporters with those of the sarcolemma or sarcoplasmic reticulum are being revealed. This has gone a long way to bringing the transporters to the forefront of cardiac research.
线粒体内游离钙（Ca(2+)）在心脏正常生理和病理状态下发挥多种关键作用，这一点现已得到广泛认可，过去二十年该领域的研究兴趣和工作成果也证明了这一点。然而，争议依然存在；例如逐搏线粒体钙瞬变的存在、Ca(2+)在调节全细胞钙信号中的作用、Ca(2+)对于需求增加时ATP供应增加是否至关重要，以及其在坏死和凋亡导致的细胞死亡中的作用，特别是在线粒体通透性转换孔的形成和缺血预处理中的作用。对于抑制钙内流或外流途径——分别为钙单向转运体（MCU）和钠/钙交换体（mNCX）——是否具有心脏保护作用也没有达成共识，这主要是由于缺乏这些转运体的特异性抑制剂。钌红、Ru360、氯硝西泮和CGP37157在分离的线粒体中都非常有效，但它们在全细胞和心脏研究中的有效性报告差异很大，这在一定程度上解释了在保护作用方面缺乏共识的原因。转运体的纯化和克隆以及更特异性抑制剂的开发，将使我们对这些看似关键但仍难以捉摸的蛋白质的作用的理解产生飞跃。然而，荧光指示剂、蛋白质和成像技术的发展意味着现在可以在完整细胞和心脏中相当特异性地测量Ca(2+)，并且线粒体钙转运体与肌膜或肌浆网钙转运体之间相互作用也正在被揭示。这在很大程度上使这些转运体成为心脏研究的前沿。
