Frequency and Selectivity of Mitochondrial Fusion Are Key to Its Quality Maintenance Function
Frequency and Selectivity of Mitochondrial Fusion Are Key to Its Quality Maintenance Function
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DOI：
10.1016/j.bpj.2008.12.3959
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发表时间：
2009-05-06
影响因子：
3.4
通讯作者：
Shirihai, Orian S.
中科院分区：
文献类型：
--
作者：
Mouli, Pradeep K.;Twig, Gilad;Shirihai, Orian S.
线粒体自噬的更新是一种重要的质量维持机制。最近的研究表明，受损线粒体成分的有效清除依赖于线粒体动力学，这是一个以频繁的融合和裂变事件为特征的过程，使线粒体成分能够在数百个线粒体个体中重新分配。提出的模拟确定了可能影响线粒体功能维持的融合和裂变的动力学参数。该程序模拟了融合和裂变事件的重复循环，其中完整和受损的线粒体内容物在融合配偶之间重新分配。再分配影响线粒体功能，从而影响每个线粒体的命运，要么注定要进行随后的融合，要么被自噬消除。我们的研究结果表明，当与裂变相结合时，融合事件可能有助于通过自噬加速受损线粒体成分的清除。该模型预测，在线粒体成分失活的持续损伤过程中，存在一个最佳的融合和裂变事件频率，可以将呼吸功能维持在稳态水平。进一步提高熔合频率可以提高损伤物的清除效率。然而，这要求融合是一个选择性的过程，在这个过程中，去极化的线粒体被排除在融合群体之外。研究发现，在损伤率升高的情况下，融合的选择性特别有益，因为它允许融合频率的增加，而不影响自噬对损伤内容物的去除。
Turnover of mitochondria by autophagy constitutes an essential quality maintenance mechanism. Recent studies have demonstrated that efficient clearance of damaged mitochondrial components depends on mitochondrial dynamics, a process characterized by frequent fusion and fission events that enable the redistribution of mitochondrial components across a population of hundreds of individual mitochondria. The presented simulation identifies kinetic parameters of fusion and fission that may influence the maintenance of mitochondrial function. The program simulated repetitive cycles of fusion and fission events in which intact and damaged mitochondrial contents were redistributed between fusion mates. Redistribution impacted mitochondrial function, thereby influencing the fate of each mitochondrion, to be either destined for a subsequent fusion or eliminated by autophagy. Our findings indicate that, when paired with fission, fusion events may serve to accelerate the removal of damaged mitochondrial components by autophagy. The model predicts the existence of an optimal frequency of fusion and fission events that can maintain respiratory function at steady-state levels amid the existence of a continuous damaging process that inactivates mitochondrial components. A further elevation of the fusion frequency can increase the clearance efficiency of damaged content. However, this requires fusion to be a selective process in which depolarized mitochondria are excluded from the fusing population. The selectivity of fusion was found to be particularly beneficial in conditions of elevated rate of damage, because it permits the increase of fusion frequency without compromising the removal of damaged content by autophagy.