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Abstract：
Mitophagy, a type of selective autophagy, specifically targets damaged mitochondria. The ULK complex regulates Parkin-mediated mitophagy, but the mechanism through which the ULK complex initiates mitophagosome formation remains unknown. The Rab7 GTPase (herein referring to Rab7a) is a key initiator of mitophagosome formation, and Ser-72 phosphorylation of Rab7 is important for this process. We have previously identified LRRK1 as a protein kinase responsible for Rab7 Ser-72 phosphorylation. In this study, we investigated the role of LRRK1 in mitophagy. We showed that LRRK1 functions downstream of ULK1 and ULK2 in Parkin-mediated mitophagy. Furthermore, we demonstrated that ectopic targeting of active LRRK1 to mitochondria is sufficient to induce the Ser-72 phosphorylation of Rab7, circumventing the requirement for ATG13, a component of the ULK complex. Thus, the ULK complex recruits LRRK1 to mitochondria by interacting with ATG13 to initiate mitophagosome formation. This study highlights the crucial role of the ULK complex-LRRK1 axis in the regulation of Parkin-mediated mitophagy.
摘要：
线粒体自噬,一种选择性自噬,特别针对受损的线粒体。ULK复合物调节Parkin介导的线粒体自噬，但ULK复合物启动线粒体吞噬体形成的机制尚不清楚。Rab7GTP酶(本文指Rab7a)是形成有丝分裂吞噬体的关键引发剂。Rab7的Ser-72磷酸化对这一过程很重要。我们先前已将LRRK1鉴定为负责Rab7Ser-72磷酸化的蛋白激酶。在这项研究中,我们研究了LRRK1在线粒体自噬中的作用。我们表明LRRK1在Parkin介导的线粒体自噬中起ULK1和ULK2下游的作用。此外，我们证明了活性LRRK1对线粒体的异位靶向足以诱导Rab7的Ser-72磷酸化，从而避免了对ULK复合物成分ATG13的需求。因此，ULK复合物通过与ATG13相互作用来将LRRK1募集到线粒体以启动线粒体吞噬体的形成。这项研究强调了ULK复合物-LRRK1轴在调节Parkin介导的线粒体自噬中的关键作用。
