Mitochondria are signaling hubs in eukaryotic cells. Here, we showed that the mitochondrial FUN14 domain–containing protein-1 (FUNDC1), an effector of Parkin-independent mitophagy, also participates in cellular plasticity by sustaining oxidative bioenergetics, buffering ROS production, and supporting cell proliferation. Targeting this pathway in cancer cells suppressed tumor growth but rendered transformed cells more motile and invasive in a manner dependent on ROS-mediated mitochondrial dynamics and mitochondrial repositioning to the cortical cytoskeleton. Global metabolomics and proteomics profiling identified a FUNDC1 interactome at the mitochondrial inner membrane, comprising the AAA+ protease, LonP1, and subunits of oxidative phosphorylation, complex V (ATP synthase). Independently of its previously identified role in mitophagy, FUNDC1 enabled LonP1 proteostasis, which in turn preserved complex V function and decreased ROS generation. Therefore, mitochondrial reprogramming by a FUNDC1-LonP1 axis controls tumor cell plasticity by switching between proliferative and invasive states in cancer.

线粒体是真核细胞中的信号中枢。在这里，我们发现线粒体 FUN14 结构域蛋白 1 (FUNDC1) 是帕金非依赖性线粒体自噬的一种效应物，它也通过维持氧化生物能量学、缓冲 ROS 产生和支持细胞增殖来参与细胞可塑性。在癌细胞中靶向该通路抑制了肿瘤生长，但以依赖于 ROS 介导的线粒体动力学和线粒体重新定位到皮质细胞骨架的方式使转化细胞更具运动性和侵袭性。全局代谢组学和蛋白质组学分析鉴定了线粒体内膜上的 FUNDC1 相互作用组，包括 AAA+ 蛋白酶、LonP1 和氧化磷酸化亚基复合物 V（ATP 合酶）。独立于其先前确定的线粒体自噬作用，FUNDC1 启用 LonP1 蛋白稳态，这反过来又保留了复杂的 V 功能并减少了 ROS 的生成。因此，FUNDC1-LonP1 轴的线粒体重编程通过在癌症的增殖和侵袭状态之间切换来控制肿瘤细胞的可塑性。