Department of Frontier Science, The University of Tokyo, Kashiwa, Chiba, Japan.
Biophys J. 2013 Jan 22;104(2):496-504. doi: 10.1016/j.bpj.2012.12.004.
In cardiomyocyte subcellular structures, colocalization of mitochondria with Ca2+ release sites is implicated in regulation of cardiac energetics by facilitating Ca2+ influx into mitochondria to modulate the tricarboxylic acid (TCA) cycle. However, current experimental techniques limit detailed examination of this regulatory mechanism. Earlier, we developed a three-dimensional (3D) finite-element cardiomyocyte model featuring a subcellular structure that integrates excitation-contraction coupling and energy metabolism. Here, using this model, we examined the influence of distance between mitochondria and Ca2+ release sites by comparing a normal (50-nm) distance model and a large (200-nm) distance model (LD). The influence of distance was minimal under a low pacing rate (0.25 Hz), but under a higher pacing rate (2 Hz), lower levels of mitochondrial Ca2+ and NADH, elevated phosphate, and suppressed force generation became apparent in the LD model. Such differences became greater when functional impairments (reduced TCA cycle activity, uncoupling effect, and failing excitation-contraction coupling) were additionally imposed. We concluded that juxtaposition of the mitochondria and the Ca2+ release sites is crucial for rapid signal transmission to maintain cardiac-energy balance. The idealized 3D model of cardiac excitation-contraction and metabolism is a powerful tool to study cardiac energetics.
在心肌细胞亚细胞结构中，线粒体与 Ca2+ 释放位点的共定位被认为在调节心脏能量学方面起作用，通过促进 Ca2+ 流入线粒体来调节三羧酸（TCA）循环。然而，当前的实验技术限制了对这种调节机制的详细研究。早些时候，我们开发了一种具有亚细胞结构的三维（3D）有限元心肌细胞模型，该模型整合了兴奋-收缩偶联和能量代谢。在这里，我们使用这个模型，通过比较正常（50nm）距离模型和大（200nm）距离模型（LD），研究了线粒体和 Ca2+ 释放位点之间的距离的影响。在低起搏率（0.25Hz）下，距离的影响最小，但在更高的起搏率（2Hz）下，LD 模型中明显出现了较低水平的线粒体 Ca2+和 NADH、升高的磷酸盐和抑制的力生成。当另外施加功能障碍（减少 TCA 循环活性、解偶联效应和兴奋-收缩偶联失败）时，这种差异变得更大。我们得出结论，线粒体和 Ca2+ 释放位点的毗邻对于快速信号传递以维持心脏能量平衡至关重要。理想化的心脏兴奋-收缩和代谢的 3D 模型是研究心脏能量学的有力工具。
