Distinct fission signatures predict mitochondrial degradation or biogenesis
Distinct fission signatures predict mitochondrial degradation or biogenesis
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DOI：
10.1038/s41586-021-03510-6
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发表时间：
2021-05-05
期刊：
影响因子：
64.8
通讯作者：
Manley, Suliana
中科院分区：
文献类型：
--
作者：
Kleele, Tatjana;Rey, Timo;Manley, Suliana
线粒体分裂是一个高度调控的过程，当它被破坏时，可以改变代谢、增殖和凋亡（1-3）。失调与神经退行性变（3,4）、心血管疾病(3)和癌症(5)有关。裂变机制的关键组成部分包括内质网(6)和肌动蛋白(7)，它们在动力蛋白相关蛋白1 (DRP1)(8)通过衔接蛋白与线粒体外膜结合（9-11）之前启动收缩，从而驱动分裂（12）。在线粒体生命周期中，裂变既可以产生新的线粒体，也可以通过线粒体自噬清除功能失调的线粒体（1,13）。目前的裂变调节模型无法解释这些双重命运是如何决定的。然而，揭示命运的决定因素是具有挑战性的，因为裂变是不可预测的，线粒体形态是异质的，其超微结构特征低于衍射极限。在这里，我们使用活细胞结构照明显微镜捕捉线粒体动力学。通过分析非洲绿猴Cos-7细胞和小鼠心肌细胞的数百次裂变，我们发现了两种功能和机制不同的裂变类型。外围区的分裂使受损物质脱落成更小的线粒体，用于线粒体自噬，而中间区的分裂导致线粒体的增殖。这两种类型均由DRP1介导，但内质网和肌动蛋白介导的预收缩和接头MFF仅控制中间区裂变。外周裂变发生在溶酶体接触之前，由线粒体外膜蛋白FIS1调控。这些不同的分子机制解释了细胞如何独立调节裂变，从而导致不同的线粒体命运。
Mitochondrial fission is ahighly regulated process that, when disrupted, can alter metabolism, proliferation and apoptosis(1-3). Dysregulation has been linked to neurodegeneration(3,4), cardiovascular disease(3) and cancer(5). Key components of the fission machinery include the endoplasmic reticulum(6) and actin(7), which initiate constriction before dynamin-related protein 1 (DRP1)(8) binds to the outer mitochondrial membrane via adaptor proteins(9-11), to drive scission(12). In the mitochondrial life cycle, fission enables both biogenesis of new mitochondria and clearance of dysfunctional mitochondria through mitophagy(1,13). Current models of fission regulation cannot explain how those dual fates are decided. However, uncovering fate determinants is challenging, as fission is unpredictable, and mitochondrial morphology is heterogeneous, with ultrastructuralfeatures that are below the diffraction limit. Here, we used live-cell structured illumination microscopy to capture mitochondrial dynamics. By analysing hundreds of fissions in African green monkey Cos-7 cells and mouse cardiomyocytes, we discovered two functionally and mechanistically distinct types of fission. Division at the periphery enables damaged material to be shed into smaller mitochondria destined for mitophagy, whereas division at the midzone leads to the proliferation of mitochondria. Both types are mediated by DRP1, but endoplasmic reticulum- and actin-mediated pre-constriction and the adaptor MFF govern only midzone fission. Peripheral fission is preceded by lysosomal contact and is regulated by the mitochondrial outer membrane protein FIS1. These distinct molecular mechanisms explain how cells independently regulate fission, leading to distinct mitochondrial fates.