Regulation of mitochondrial fission by GIPC-mediated Drp1 retrograde transport
AffiliationDepartment of Pharmacology, University of Arizona
Department of Chemistry & Biochemistry, University of Arizona
Department of Medicine, University of Arizona
Cancer Center, University of Arizona
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CitationRamonett, A., Kwak, E.-A., Ahmed, T., Flores, P. C., Ortiz, H. R., Lee, Y. S., Vanderah, T. W., Largent-Milnes, T., Kashatus, D. F., Langlais, P. R., Mythreye, K., & Lee, N. Y. (2022). Regulation of mitochondrial fission by GIPC-mediated Drp1 retrograde transport. Molecular Biology of the Cell.
JournalMolecular biology of the cell
RightsCopyright © 2022 Ramonett et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial-Share Alike 4.0 International Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/4.0).
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AbstractDynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission, a large cytoplasmic GTPase recruited to the mitochondrial surface via transmembrane adaptors to initiate scission. While Brownian motion likely accounts for the local interactions between Drp1 and the mitochondrial adaptors, how this essential enzyme is targeted from more distal regions like the cell periphery remains unknown. Based on proteomic interactome screening and cell-based studies, we report that GAIP/RGS19-interacting protein (GIPC) mediates the actin-based retrograde transport of Drp1 toward the perinuclear mitochondria to enhance fission. Drp1 interacts with GIPC through its atypical C-terminal PDZ-binding motif. Loss of this interaction abrogates Drp1 retrograde transport resulting in cytoplasmic mislocalization and reduced fission despite retaining normal intrinsic GTPase activity. Functionally, we demonstrate that GIPC potentiates the Drp1-driven proliferative and migratory capacity in cancer cells. Together, these findings establish a direct molecular link between altered GIPC expression and Drp1 function in cancer progression and metabolic disorders.
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VersionFinal published version
Except where otherwise noted, this item's license is described as Copyright © 2022 Ramonett et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial-Share Alike 4.0 International Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/4.0).
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