MITOCHONDRIAL ENERGY-PRODUCTION AND CATION CONTROL IN MYOCARDIAL-ISCHEMIA AND REPERFUSION
MITOCHONDRIAL ENERGY-PRODUCTION AND CATION CONTROL IN MYOCARDIAL-ISCHEMIA AND REPERFUSION
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DOI：
10.1007/bf00795415
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发表时间：
1993-09-01
影响因子：
9.5
通讯作者：
VISIOLI, O
中科院分区：
文献类型：
--
作者：
FERRARI, R;PEDERSINI, P;VISIOLI, O
在心脏中，线粒体对细胞存活起着两个重要的作用：ATP合成和Ca2+稳态的维持。这两个过程是由相同的能量源驱动的：H+电化学梯度（DELTAmuH），这是由电子沿线粒体内膜传递产生的。在有氧生理条件下，线粒体不参与细胞质Ca2+的搏动调节，尽管已经描述了线粒体基质中Ca2+的瞬态。线粒体Ca2+浓度的增加刺激克雷布斯循环和NADH氧化还原电位，从而刺激ATP合成。然而，在病理条件下，线粒体Ca2+转运和超载可能导致一系列恶性循环，导致不可逆的细胞损伤。线粒体Ca2+积累导致内膜对溶质的通透性发生深刻改变，导致严重的线粒体肿胀。此外，Ca2+转运优先于ATP合成，并抑制DELTAmuH对能量产生的利用。这些过程对于理解长期缺血后心肌再灌注过程中导致不可逆细胞损伤的分子事件序列非常重要。在缺血期间，细胞内Ca2+稳态发生改变，线粒体能够缓冲胞质内Ca2+，这表明它们保留了Ca2+运输能力。因此，一旦分离，即使在长时间缺血后，大多数线粒体能够利用氧气进行ATP磷酸化。再灌注后分离的线粒体结构改变，含有大量Ca2+，产生过量的氧自由基，其膜孔受到刺激，氧化磷酸化能力被不可逆地破坏。最有可能的是，再灌注提供氧气以重新激活线粒体呼吸，但也导致大量Ca2+流入细胞质中，这是肌层损伤的结果。因此，线粒体Ca2+运输以最大速率受到刺激，因此，ATP合成和Ca2+内流之间的平衡向Ca2+内流转移，同时失去ATP合成的能力。
In the heart mitochondria exert two roles essential for cell survival: ATP synthesis and maintainance of Ca2+ homeostasis. These two processes are driven by the same energy source: the H+ electrochemical gradient (DELTAmuH) which is generated by electron transport along the inner mitochondrial membrane.Under aerobic physiological condition mitochondria do not contribute to the beat to beat regulation of cytosolic Ca2+, although Ca2+ transient in mitochondrial matrix has been described. Increases in mitochondrial Ca2+ of mumolars concentration stimulate the Krebs cycle and NADH redox potential and, therefore, ATP synthesis.Under pathological conditions, however, mitochondrial Ca2+ transport and overload might cause a series of vicious cycles leading to irreversible cell damage.Mitochondrial Ca2+ accumulation causes profound alterations in permeability of the inner membrane to solutes, leading to severe mitochondrial swelling. In addition Ca2+ transport takes precedence over ATP synthesis and inhibits utilization of DELTAmuH for energy production.These processes are important to understand the sequence of the molecular events occurring during myocardial reperfusion after prolonged ischaemia which lead to irreversible cell damage. During ischaemia an alteration of intracellular Ca2+ homeostasis occurs and mitochondria are able to buffer cytosolic Ca2+, suggesting that they retain the Ca2+ transporting capacity. Accordingly, once isolated, even after prolonged ischaemia, the majority of the mitochondria is able to use oxygen for ATP phosphorylation.When isolated after reperfusion, mitochondria are structurally altered, contain large quantities of Ca2+, produce excess of oxygen free radicals, their membrane pores are stimulated and the oxidative phosphorylation capacity is irreversibly disrupted. Most likely, reperfusion provides oxygen to reactivate mitochondrial respiration but also causes large influx of Ca2+ in the cytosol as result of sarcolemmal damage. Mitochondrial, Ca2+ transport is therefore stimulated at maximal rates and, as consequence, the equilibrium between ATP synthesis and Ca2+ influx is shifted towards Ca2+ influx with loss of the ability of ATP synthesis.