Omegasome-proximal PtdIns(4,5)P2 couples F-actin mediated mitoaggregate disassembly with autophagosome formation during mitophagy
Omegasome-proximal PtdIns(4,5)P2 couples F-actin mediated mitoaggregate disassembly with autophagosome formation during mitophagy
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DOI：
10.1038/s41467-019-08924-5
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发表时间：
2019-02-27
影响因子：
16.6
通讯作者：
Yang, Wei Yuan
中科院分区：
文献类型：
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作者：
Hsieh, Cheng-Wei;Yang, Wei Yuan
细胞通过自噬将从蛋白质到聚集体和细胞器的各种底物隔离到自噬小体中进行溶酶体降解，从而调节自身的动态平衡。在这些过程中，细胞需要在底物重塑和自噬小体形成之间进行协调，以便有效地吞噬。我们发现，在Parkin介导的有丝分裂中，被翻转的线粒体首先成为葡萄状的有丝分裂聚集体，然后通过放线肌球系统将其分解成更小的片段。在拆解步骤中，我们观察到线粒体附近空间相关的环状F-肌动蛋白和BATS标记的自噬起始位点的同步形成，这表明在有丝分裂过程中底物尺寸减小和自噬小体形成之间存在协调。有趣的是，PtdIns(4，5)P-2而不是PtdIns(3)P调节这种与有丝分裂相关的环状F-肌动蛋白和BATS-位点的形成。PtdIns(4，5)P-2在omegasome附近的选择性缺失，参与自噬小体形成的内质网(ER)亚域，损害有丝分裂。我们的发现证明了靠近omegasome的PtdIns(4，5)P-2池的存在，并且在Parkin介导的有丝分裂过程中，它们协调了有丝分裂聚集体的分解和自噬的启动。
Cells govern their homeostasis through autophagy by sequestering substrates, ranging from proteins to aggregates and organelles, into autophagosomes for lysosomal degradation. In these processes cells need to coordinate between substrate remodeling and autophagosome formation for efficient engulfment. We found that in Parkin-mediated mitophagy, mitochondria to be turned over first become grape-like mitoaggregates, followed by their disassembly into smaller pieces via the actinomyosin system. At the disassembly step, we observed spatially-associated, synchronous formation of circular F-actin and BATS-labeled autophagy initiation sites near mitochondria, suggesting coordination between substrate downsizing and autophagosome formation during mitophagy. Interestingly, PtdIns(4,5)P-2, instead of PtdIns(3)P, regulates this mitophagy-associated formation of circular F-actin and BATS-sites. Selective depletion of PtdIns(4,5)P-2 near omegasomes, the endoplasmic reticulum (ER) subdomains involved in autophagosome formation, impaired mitoaggregate disassembly. Our findings demonstrate the presence of a pool of PtdIns(4,5)P-2 adjacent to omegasomes, and that they coordinate mitoaggregate disassembly with autophagy initiation during Parkin-mediated mitophagy.