The mitophagy effector FUNDC1 controls mitochondrial reprogramming and cellular plasticity in cancer cells
- 28 July 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Signaling
- Vol. 13 (642)
- https://doi.org/10.1126/scisignal.aaz8240
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.Keywords
Funding Information
- National Cancer Institute (P01 CA140043)
- National Cancer Institute (P01 CA140043)
- National Cancer Institute (P01 CA140043)
- National Cancer Institute (R35 CA220446)
- National Cancer Institute (R50 CA221838)
- National Cancer Institute (R50 CA211199)
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