Intermitochondrial signaling regulates the uniform distribution of stationary mitochondria in axons
Intermitochondrial signaling regulates the uniform distribution of stationary mitochondria in axons
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DOI：
10.1016/j.mcn.2022.103704
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发表时间：
2022-02-17
影响因子：
3.5
通讯作者：
Konishi, Yoshiyuki
中科院分区：
文献类型：
--
作者：
Matsumoto, Nozomu;Hori, Ikuma;Konishi, Yoshiyuki
在中枢神经系统（CNS）中，许多神经元发育轴突乔木，这对信息处理至关重要。以往的研究表明，未成熟的轴突含有运动和静止的线粒体，它们的平衡对于轴突的分支是重要的。然而，神经元决定静止线粒体的位置以及它们的周转的机制仍有待阐明。我们观察到，在原代培养的神经元和组织中，静止的线粒体斑点沿着无髓鞘和非突触轴突的分布不是随机的，而是相对均匀的。有趣的是，虽然每个线粒体斑点的位置随着时间的推移而变化，但整体分布保持一致。此外，KillerRed介导的发色团辅助光失活（卡利）对线粒体的局部失活抑制了相邻轴突区域中线粒体斑点的移位，这表明功能性线粒体增强了附近其他线粒体的运动性。ATP：ADP传感器PercevalHR的信号表明，线粒体周围的ATP：ADP比率相对较高，并且用提供ATP的磷酸肌酸（PCr）处理轴突减少了由局部线粒体失活引起的不动线粒体。在一个数学模型中，我们发现由线粒体产生的ATP梯度，以及线粒体运动的ATP依赖性调节可以建立均匀的线粒体分布。这些观察结果表明，中枢神经系统中的轴突具有均匀分布线粒体的系统，并且线粒体信号传导有助于调节。此外，我们的研究结果表明，ATP可能是介导信号的分子之一。
In the central nervous system (CNS), many neurons develop axonal arbors that are crucial for information processing. Previous studies have demonstrated that premature axons contain motile and stationary mitochondria, and their balance is important for axonal arborization. However, the mechanisms by which neurons determine the positions of stationary mitochondria as well as their turnover remain to be elucidated. We observed that the distribution of stationary mitochondrial spots along the unmyelinated and nonsynaptic axons is not random but rather relatively uniform both in primary cultured neurons and in tissues. Intriguingly, whereas the positions of each mitochondrial spot changed over time, the overall distribution remained uniform. In addition, local inactivation of mitochondria by KillerRed mediated chromophore-assisted light inactivation (CALI) inhibited the translocation of mitochondrial spots in adjacent axonal regions, suggesting that functional mitochondria enhance the motility of other mitochondria in the vicinity. Signals of ATP:ADP sensor, PercevalHR indicated that the ATP:ADP ratio was relatively high around mitochondria, and treating axons with phosphocreatine (PCr), which supplies ATP, reduced the immobile mitochondria induced by the local mitochondrial inactivation. In a mathematical model, we found that the ATP gradient generated by mitochondria, and ATP dependent regulation of mitochondrial motility could establish uniform mitochondrial distribution. These observations suggest that axons in the CNS possess the system that distributes mitochondria uniformly, and intermitochondrial signaling contribute to the regulation. In addition, our results suggest the possibility that ATP might be one of the molecules mediating the signaling.