Mitochondrial Networks in Cardiac Myocytes Reveal Dynamic Coupling Behavior
Mitochondrial Networks in Cardiac Myocytes Reveal Dynamic Coupling Behavior
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DOI：
10.1016/j.bpj.2015.01.040
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发表时间：
2015-04-21
影响因子：
3.4
通讯作者：
Armoundas, Antonis A.
中科院分区：
文献类型：
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作者：
Kurz, Felix T.;Derungs, Thomas;Armoundas, Antonis A.
线粒体内膜电位（δ psi(m)）的振荡行为在氧化或代谢应激的细胞中很常见。在心肌细胞中，活性氧（ROS）对内膜孔的激活是介导间歇性线粒体偶联的主要因素，ROS诱导的ROS释放已被证明是Delta psi(m)去极化传播波以及网络中Delta psi(m)同步极限环振荡的基础。Delta psi(m)不稳定性对心脏电生理、Ca2+处理甚至细胞存活的功能影响，受到这种间歇性线粒体偶联程度的强烈影响。在这里，我们采用最近开发的基于小波的分析方法来研究不同底物如何影响心肌细胞中的线粒体偶联，并且我们还确定了完整灌注心脏中心室细胞中线粒体的振荡偶联特性。结果表明，δ psi(m)振荡频率与线粒体簇的大小成反比，并取决于局部间歇线粒体耦合的强度。采用基于Kuramoto模型的随机相位模型，可以定量地确定耦合振荡网络的时变耦合常数。不同底物的聚类大小-频率关系不同，线粒体偶联常数也不同，葡萄糖(7.78 × 10(-2) +/- 0.98 × 10（-2) s(-1)）和丙酮酸盐(7.49 × 10(-2) +/- 1.65 × 10（-2) s(-1)）明显大于乳酸(4.83 × 10(-2) +/- 1.25 × 10（-2) s(-1)）或β -羟基丁酸盐(4.11 × 10(-2) +/- 0.62 × 10（-2) s(-1)）。研究结果表明，线粒体时空耦合和振荡行为受到底物选择的影响，可能是通过对ROS/氧化还原平衡的不同影响。特别是葡萄糖-灌注产生较强的间歇线粒体偶联和时间振荡稳定性。特定分解代谢途径的病理改变，已知发生在心血管疾病的进展过程中，因此可能导致线粒体网络对氧化应激和δ psi(m)不稳定的敏感性改变，最终导致器官水平功能障碍。
Oscillatory behavior of mitochondrial inner membrane potential (Delta psi(m)) is commonly observed in cells subjected to oxidative or metabolic stress. In cardiac myocytes, the activation of inner membrane pores by reactive oxygen species (ROS) is a major factor mediating intermitochondrial coupling, and ROS-induced ROS release has been shown to underlie propagated waves of Delta psi(m) depolarization as well as synchronized limit cycle oscillations of Delta psi(m) in the network. The functional impact of Delta psi(m) instability on cardiac electrophysiology, Ca2+ handling, and even cell survival, is strongly affected by the extent of such intermitochondrial coupling. Here, we employ a recently developed wavelet-based analytical approach to examine how different substrates affect mitochondrial coupling in cardiac cells, and we also determine the oscillatory coupling properties of mitochondria in ventricular cells in intact perfused hearts. The results show that the frequency of Delta psi(m) oscillations varies inversely with the size of the oscillating mitochondrial cluster, and depends on the strength of local intermitochondrial coupling. Time-varying coupling constants could be quantitatively determined by applying a stochastic phase model based on extension of the well-known Kuramoto model for networks of coupled oscillators. Cluster size-frequency relationships varied with different substrates, as did mitochondrial coupling constants, which were significantly larger for glucose (7.78 x 10(-2) +/- 0.98 x 10(-2) s(-1)) and pyruvate (7.49 x 10(-2) +/- 1.65 x 10(-2) s(-1)) than lactate (4.83 x 10(-2) +/- 1.25 x 10(-2) s(-1)) or beta-hydroxybutyrate (4.11 x 10(-2) +/- 0.62 x 10(-2) s(-1)). The findings indicate that mitochondrial spatiotemporal coupling and oscillatory behavior is influenced by substrate selection, perhaps through differing effects on ROS/redox balance. In particular, glucose-perfusion generates strong intermitochondrial coupling and temporal oscillatory stability. Pathological changes in specific catabolic pathways, which are known to occur during the progression of cardiovascular disease, could therefore contribute to altered sensitivity of the mitochondrial network to oxidative stress and emergent Delta psi(m) instability, ultimately scaling to produce organ level dysfunction.