The fateful encounter of mitochondria with calcium: How did it happen?
The fateful encounter of mitochondria with calcium: How did it happen?
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DOI：
10.1016/j.bbabio.2010.03.024
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发表时间：
2010-06-01
影响因子：
4.3
通讯作者：
Carafoli, Ernesto
中科院分区：
文献类型：
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作者：
Carafoli, Ernesto
20世纪50年代的许多发现间接表明线粒体可以积累Ca 2+。在1961年，这一现象被分离的线粒体直接证明：摄取过程是由呼吸链活性或添加的ATP水解驱动的。它可以伴随着无机磷酸盐的同时吸收，在这种情况下，在基质中形成羟基磷灰石沉淀，缓冲其游离Ca 2+浓度。在20世纪60年代和70年代建立了摄取过程的性质：Ca 2+的摄取在尚未被分子鉴定的载体上以非稳态方式发生，并通过Na+/Ca 2+反向转运蛋白从线粒体释放。H+/Ca 2+释放交换器也被发现在某些线粒体类型中起作用。渗透性转换孔后来也被发现介导的Ca 2+从线粒体流出。在线粒体基质中，发现两个TCA循环酶和丙酮酸脱氢酶磷酸磷酸酶在基质中通过跨内膜的Ca 2+循环来调节。在细胞质Ca 2+超载的条件下，线粒体可以储存大量沉淀的Ca 2 +-磷酸盐，从而允许细胞在Ca 2+紧急情况下存活。发现摄取过程对Ca 2+具有非常低的亲和力：由于细胞质中Ca 2+的体积浓度在低至中nM范围内，因此越来越难以假定线粒体在调节细胞质Ca 2+中的作用。然而，许多研究结果表明，能量相关的Ca 2+转运有效地发生在各种组织的线粒体原位。这个悖论直到20世纪90年代才得到解决，当时人们发现细胞质中的Ca 2+浓度并不均匀：线粒体周围的微池是由激动剂促进的Ca 2+从邻近储存中释放而产生的，其中Ca 2+浓度足够高，可以激活低亲和力的线粒体单向转运体。因此，线粒体作为细胞质Ca 2+（不仅是其自身内部Ca 2+）的重要调节剂重新回到中心舞台。发现它们的Ca 2+摄取系统对细胞质Ca 2+需求的反应非常迅速，甚至在150-200毫秒的时间尺度内，如心脏的收缩和舒张。线粒体Ca 2+转运领域的一个重要的最新进展是其参与疾病过程。Ca 2+信号传导缺陷现在在疾病的发病机制中越来越重要，例如，神经退行性疾病由于线粒体现在已经恢复了在细胞质Ca 2+调节中的中心作用，因此已经发现其Ca 2+控制系统的功能障碍参与许多疾病过程的发病机制。(C)出版社：Elsevier B. V.
A number of findings in the 1950s had offered indirect indications that mitochondria could accumulate Ca2+. In 1961, the phenomenon was directly demonstrated using isolated mitochondria: the uptake process was driven by respiratory chain activity or by the hydrolysis of added ATP. It could be accompanied by the simultaneous uptake of inorganic phosphate, in which case precipitates of hydroxyapatite were formed in the matrix, buffering its free Ca2+ concentration. The properties of the uptake process were established in the 1960s and 1970s: the uptake of Ca2+ occurred electrophoretically on a carrier that has not yet been molecularly identified, and was released from mitochondria via a Na+/Ca2+ antiporter. A H+/Ca2+ release exchanger was also found to operate in some mitochondrial types. The permeability transition pore was later also found to mediate the efflux of Ca2+ from mitochondria. In the mitochondrial matrix two TCA cycle dehydrogenases and pyruvate dehydrogenase phosphate phosphatase were found to be regulated in the matrix by the cycling of Ca2+ across the inner membrane. In conditions of cytoplasmic Ca2+ overload mitochondria could store for a time large amounts of precipitated Ca2+-phosphate, thus permitting cells to survive situations of Ca2+ emergency. The uptake process was found to have very low affinity for Ca2+: since the bulk concentration of Ca2+ in the cytoplasm is in the low to mid-nM range, it became increasingly difficult to postulate a role of mitochondria in the regulation of cytoplsmic Ca2+. A number of findings had nevertheless shown that energy linked Ca2+ transport occurred efficiently in mitochondria of various tissues in situ. The paradox was only solved in the 1990s, when it was found that the concentration of Ca2+ in the cytoplasm is not uniform: perimitochondrial micropools are created by the agonist-promoted discharge of Ca2+ from vicinal stores in which the concentration of Ca2+ is high enough to activate the low affinity mitochondrial uniporter. Mitochondria thus regained center stage as important regulators of cytoplasmic Ca2+ (not only of their own internal Ca2+). Their Ca2+ uptake systems was found to react very rapidly to cytoplasmic Ca2+ demands, even in the 150-200 msec time scale of processes like the contraction and relaxation of heart. An important recent development in the area of mitochondrial Ca2+ transport is its involvement in the disease process. Ca2+ signaling defects are now gaining increasing importance in the pathogenesis of diseases, e.g., neurodegenerative diseases. Since mitochondria have now regained a central role in the regulation of cytoplasmic Ca2+, dysfunctions of their Ca2+ controlling systems have expectedly been found to be involved in the pathogenesis of numerous disease processes. (C) 2010 Published by Elsevier B.V.