Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan.
J Cell Sci. 2022 Dec 1;135(23). doi: 10.1242/jcs.260395. Epub 2022 Dec 7.
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.
线粒体自噬是一种选择性自噬，特异性靶向损伤的线粒体。ULK 复合物调节 Parkin 介导的线粒体自噬，但 ULK 复合物启动线粒体自噬体形成的机制尚不清楚。Rab7 GTPase（在此指 Rab7a）是线粒体自噬体形成的关键启动子，Rab7 的 Ser-72 磷酸化对这一过程很重要。我们之前已经确定 LRRK1 是负责 Rab7 Ser-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。结果表明，LRRK1 在 Parkin 介导的线粒体自噬中位于 ULK1 和 ULK2 的下游。此外，我们证明了将活性 LRRK1 异位靶向线粒体足以诱导 Rab7 的 Ser-72 磷酸化，从而绕过 ULK 复合物的组成部分 ATG13 的需求。因此，ULK 复合物通过与 ATG13 相互作用将 LRRK1 招募到线粒体来启动线粒体自噬体的形成。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。
