Mitochondrial network determines intracellular ROS dynamics and sensitivity to oxidative stress through switching inter-mitochondrial messengers.
Mitochondrial network determines intracellular ROS dynamics and sensitivity to oxidative stress through switching inter-mitochondrial messengers.
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DOI：
10.1371/journal.pone.0023211
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Choi C
中科院分区：
文献类型：
--
作者：
Park J;Lee J;Choi C
由活性氧(ROS)引起的氧化应激可引起线粒体膜内电位的快速去极化，进而导致氧化磷酸化的损伤。损伤的线粒体产生更多的ROS，特别是超氧阴离子(O2-−)和过氧化氢(H_2O_2)，它们通过激活线粒体间的信号网络来加强线粒体驱动的ROS的繁殖，即所谓的ROS诱导的ROS释放。因此，只有一小部分线粒体的功能丧失可能最终会通过这个正反馈回路影响细胞的存活。由于ROS在生物环境中是非常短暂的分子，线粒体网络的动态，如密度、数量和空间分布，可以影响线粒体驱动的ROS的传播。为了解决这个问题，我们使用基于代理的建模方法建立了一个数学模型，并测试了不同条件下线粒体网络动态对线粒体RIRR的影响。模拟结果表明，细胞内ROS的信号模式，如ROS的传播速度和氧化应激脆弱性，都受到线粒体网络动力学的严重影响。线粒体分布、密度、活性和大小的线粒体网络动力学可以在一定条件下介导线粒体间信号转导，并决定ROS信号模式的一致性。我们进一步阐明了这些作用的潜在机制，即参与ROS信号转导的主要信使分子的转换。如果相邻线粒体之间的平均距离较大或线粒体分布变得随机，ROS信号网络的信使分子可以从O2−切换到H2O2。在这种情况下，线粒体驱动的ROS的传播可以通过引入过量的胞质谷胱甘肽过氧化物酶1而被有效地阻止，而胞质超氧化物歧化酶的引入则没有影响。综上所述，这些结果表明线粒体网络动力学是通过改变关键信使分子来决定细胞对RIRR的反应的主要决定因素。
Oxidative stresses caused by reactive oxygen species (ROS) can induce rapid depolarization of inner mitochondrial membrane potential and subsequent impairment of oxidative phosphorylation. Damaged mitochondria produce more ROS, especially the superoxide anion (O2 −) and hydrogen peroxide (H2O2), which potentiate mitochondria-driven ROS propagation, so-called ROS-induced ROS release (RIRR), via activation of an inter-mitochondria signaling network. Therefore, loss of function in only a fraction of mitochondria might eventually affect cell viability through this positive feedback loop. Since ROS are very short-lived molecules in the biological milieu, mitochondrial network dynamics, such as density, number, and spatial distribution, can affect mitochondria-driven ROS propagation. To address this issue, we developed a mathematical model using an agent-based modeling approach, and tested the effect of mitochondrial network dynamics on RIRR for mitochondria under various conditions. Simulation results show that the intracellular ROS signaling pattern, such as ROS propagation speed and oxidative stress vulnerability, are critically affected by mitochondrial network dynamics. Mitochondrial network dynamics of mitochondrial distribution, density, activity, and size can mediate inter-mitochondrial signaling under certain conditions and determine the identity of the ROS signaling pattern. We further elucidated the potential mechanism of these actions, i.e., conversion of major messenger molecules involved in ROS signaling. If the average distance between neighboring mitochondria is large or mitochondrial distribution becomes randomized, messenger molecule of the ROS signaling network can be switched from O2 − to H2O2. In this case, mitochondria-driven ROS propagation is efficiently blocked by introduction of excess cytosolic glutathione peroxidase 1, while introduction of cytosolic superoxide dismutase has no effect. Together, these results suggest that mitochondrial network dynamics is a major determinant for cellular responses to RIRR through changing the key messenger molecules.
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DOI：
10.1073/pnas.0307156101
发表时间：
2004-03-30
影响因子：
11.1
作者：
Aon, MA;Cortassa, S;O'Rourke, B
通讯作者：
O'Rourke, B
DOI：
10.1073/pnas.072081299
发表时间：
2002-05-14
影响因子：
11.1
作者：
Bankes, SC
通讯作者：
Bankes, SC
影响因子：
9.3
作者：
Sharma, A;Singh, M
通讯作者：
Singh, M
影响因子：
3.4
作者：
Brady, NR;Elmore, SP;Westerhoff, HV
通讯作者：
Westerhoff, HV
影响因子：
3.4
作者：
Cortassa, S;Aon, MA;O'Rourke, B
通讯作者：
O'Rourke, B