Department of Molecular Biology, Faculty of Medicine, Hokkaido University, 060-8638, Sapporo, Japan.
Global Institution for Collaborative Research and Education, Hokkaido University, 060-8638, Sapporo, Japan.
Nat Commun. 2018 Jul 11;9(1):2682. doi: 10.1038/s41467-018-05087-7.
Mitochondria dynamically alter their subcellular localization during cell movement, although the underlying mechanisms remain largely elusive. The small GTPase Arf6 and its signaling pathway involving AMAP1 promote cell invasion via integrin recycling. Here we show that the Arf6-AMAP1 pathway promote the anterograde trafficking of mitochondria. Blocking the Arf6-based pathway causes mitochondrial aggregation near the microtubule-organizing center, and subsequently induces detrimental reactive oxygen species (ROS) production, likely via a mitochondrial ROS-induced ROS release-like mechanism. The Arf6-based pathway promotes the localization of ILK to focal adhesions to block RhoT1-TRAK2 association, which controls mitochondrial retrograde trafficking. Blockade of the RhoT1-TRAK1 machinery, rather than RhoT1-TRAK2, impairs cell invasion, but not two-dimensional random cell migration. Weakly or non-invasive cells do not notably express TRAK proteins, whereas they clearly express their mRNAs. Our results identified a novel association between cell movement and mitochondrial dynamics, which is specific to invasion and is necessary for avoiding detrimental ROS production.
线粒体在细胞运动过程中动态改变其亚细胞定位，但潜在的机制在很大程度上仍未被揭示。小 GTPase Arf6 及其涉及 AMAP1 的信号通路通过整合素循环促进细胞侵袭。在这里，我们显示 Arf6-AMAP1 通路促进线粒体的正向运输。阻断基于 Arf6 的通路会导致线粒体在微管组织中心附近聚集，随后诱导有害的活性氧（ROS）产生，可能通过线粒体 ROS 诱导的 ROS 释放样机制。基于 Arf6 的通路促进 ILK 定位于焦点黏附，以阻断 RhoT1-TRAK2 关联，从而控制线粒体逆行运输。阻断 RhoT1-TRAK1 机制而不是 RhoT1-TRAK2 会损害细胞侵袭，但不会损害二维随机细胞迁移。弱侵袭或非侵袭性细胞不会明显表达 TRAK 蛋白，而它们清楚地表达其 mRNA。我们的结果确定了细胞运动和线粒体动力学之间的新关联，这种关联是侵袭特有的，对于避免有害的 ROS 产生是必要的。
