State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, China.
Sci Rep. 2016 Sep 13;6:32933. doi: 10.1038/srep32933.
Mitochondria are highly dynamic organelles undergoing constant network reorganization and exhibiting stochastic signaling events in the form of mitochondrial flashes (mitoflashes). Here we investigate whether and how mitochondrial network dynamics regulate mitoflash biogenesis and signaling. We found that mitoflash frequency was largely invariant when network fragmentized or redistributed in the absence of mitofusin (Mfn) 1, Mfn2, or Kif5b. However, Opa1 deficiency decreased spontaneous mitoflash frequency due to superimposing changes in respiratory function, whereas mitoflash response to non-metabolic stimulation was unchanged despite network fragmentation. In Drp1- or Mff-deficient cells whose mitochondria hyperfused into a single whole-cell reticulum, the frequency of mitoflashes of regular amplitude and duration was again unaltered, although brief and low-amplitude "miniflashes" emerged because of improved detection ability. As the network reorganized, however, the signal mass of mitoflash signaling was dynamically regulated in accordance with the degree of network connectivity. These findings demonstrate a novel functional role of mitochondrial network dynamics and uncover a magnitude- rather than frequency-modulatory mechanism in the regulation of mitoflash signaling. In addition, our data support a stochastic trigger model for the ignition of mitoflashes.
线粒体是高度动态的细胞器，不断进行网络重组，并以线粒体闪烁（mitoflashes）的形式表现出随机信号事件。在这里，我们研究了线粒体网络动态是否以及如何调节mitoflash 的生物发生和信号转导。我们发现，当线粒体融合蛋白 1（Mfn1）、Mfn2 或 Kif5b 缺失导致网络碎片化或重新分布时，mitoflash 的频率基本不变。然而，由于呼吸功能的叠加变化，Opa1 缺失会降低自发的 mitoflash 频率，而尽管网络碎片化，mitoflash 对非代谢刺激的反应仍保持不变。在 Drp1 或 Mff 缺陷细胞中，线粒体超融合成单个全细胞网状结构，规则幅度和持续时间的 mitoflash 频率再次保持不变，尽管由于检测能力提高而出现短暂且低幅度的“miniflashes”。然而，随着网络的重新组织，mitoflash 信号的信号质量根据网络连接程度动态调节。这些发现表明线粒体网络动态具有新的功能作用，并揭示了在调节 mitoflash 信号转导中，幅度而不是频率调节的机制。此外，我们的数据支持了 mitoflashes 点火的随机触发模型。
