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Suppressing metastasis for proliferation
Cancer cells must halt proliferative pathways and reprogram their morphology and metabolism to metastasize from the primary tumor. Li et al. found that FUNDC1 played a role in suppressing the switch from proliferation to metastasis in cancer cells of different tissue origins. In mice, xenografts formed from FUNDC1-deficient cancer cells developed into smaller primary tumors but were more likely to metastasize. FUNDC1 promoted proliferation by suppressing fission and relocalization of mitochondria to the leading edge of migrating cancer cells, enhancing oxidative metabolism, and limiting mitochondrial ROS production. These effects required the stabilization of the mitochondrial protease LonP1 and components of the mitochondrial ATP synthase complex (also known as complex V) by FUNDC1. By regulating mitochondrial morphology, localization, and function, FUNDC1 confers the cellular and metabolic features that support cancer cell proliferation.
Abstract
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.
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