BACKGROUND The PINK1:Parkin pathway regulates the autophagic removal of damaged and dysfunctional mitochondria. While the response of this pathway to complete loss of ΔΨm, as caused by high concentrations of mitochondrial ionophores, has been well characterized, it remains unclear how the pathway makes coherent decisions about whether to keep or purge mitochondria in situations where ΔΨm is only partially lost or exhibits fluctuations, as has been observed in response to certain types of cellular stress. RESULTS To investigate the responses of the PINK1:Parkin pathway to mitochondrial insults of different magnitude and duration, controlled titration of the mitochondrial protonophore, CCCP, was used to manipulate ΔΨm in live cells, and the dynamics of PINK1 and Parkin recruitment was measured by fluorescence microscopy. In contrast to the stable accumulation of PINK1 and Parkin seen at completely depolarized mitochondria, partial depolarization produced a transient pulse of PINK1 stabilization and rapid loss, which was driven by small fluctuations in ΔΨm. As the rate of Parkin dissociation from the mitochondria and phospho-polyubiquitin chain removal was comparatively slow, repetitive pulses of PINK1 were able to drive a slow step-wise accumulation of Parkin and phospho-polyubiquitin leading to deferred mitophagy. CONCLUSION These data suggest that the PINK1:Parkin mitophagy pathway is able to exhibit distinct dynamic responses to complete and partial mitochondrial depolarization. In this way, the pathway is able to differentiate between irretrievably damaged mitochondria and those showing signs of dysfunction, promoting either rapid or delayed autophagy, respectively.

中文翻译：

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通过PINK1：Parkin途径对线粒体应激信号进行时间整合。

背景技术PINK1：Parkin途径调节受损和功能异常的线粒体的自噬清除。尽管已经很好地表征了由高浓度的线粒体离子载体引起的该途径对ΔΨm完全丧失的响应，但仍不清楚该途径如何在仅部分丧失ΔΨm的情况下做出有关保持或清除线粒体的一致决定。或表现出波动，正如对某些类型的细胞应激反应所观察到的那样。结果为研究PINK1：Parkin途径对不同幅度和持续时间的线粒体损伤的反应，控制线粒体质子体CCCP的滴定控制了活细胞中的ΔΨm，并通过荧光测量了PINK1和Parkin募集的动力学显微镜检查。与在完全去极化的线粒体上看到的PINK1和Parkin的稳定积累相反，部分去极化产生了PINK1稳定的瞬态脉冲和快速损耗，这是由ΔΨm的小波动驱动的。由于Parkin从线粒体解离的速度和磷酸-多聚泛素链的去除相对较慢，因此，PINK1的重复脉冲能够驱动Parkin和磷酸-多聚泛素的缓慢逐步积累，从而导致线粒体递延。结论这些数据表明，PINK1：Parkin的线粒体吞噬途径能够对完全和部分线粒体去极化表现出不同的动态响应。这样，该途径可以区分无法修复的线粒体和表现出功能障碍迹象的线粒体，从而促进快速自噬或延迟自噬，