title: APC binds the Miro/Milton motor complex to stimulate transport of mitochondria to the plasma membrane.
abstract: Mutations in adenomatous polyposis coli (APC) disrupt regulation of Wnt signaling, mitosis, and the cytoskeleton. We describe a new role for APC in the transport of mitochondria. Silencing of wild-type APC by small interfering RNA caused mitochondria to redistribute from the cell periphery to the perinuclear region. We identified novel APC interactions with the mitochondrial kinesin-motor complex Miro/Milton that were mediated by the APC C-terminus. Truncating mutations in APC abolished its ability to bind Miro/Milton and reduced formation of the Miro/Milton complex, correlating with disrupted mitochondrial distribution in colorectal cancer cells that could be recovered by reconstitution of wild-type APC. Using proximity ligation assays, we identified endogenous APC-Miro/Milton complexes at mitochondria, and live-cell imaging showed that loss of APC slowed the frequency of anterograde mitochondrial transport to the membrane. We propose that APC helps drive mitochondria to the membrane to supply energy for cellular processes such as directed cell migration, a process disrupted by cancer mutations.
authors.affiliation: Centre for Cancer Research, Westmead Institute for Medical Research, University of Sydney, Westmead, NSW 2145, Australia.
authors.forename: Kate M
authors.initials: KM
authors.lastname: Mills
authors.affiliation: Centre for Cancer Research, Westmead Institute for Medical Research, University of Sydney, Westmead, NSW 2145, Australia beric.henderson@sydney.edu.au mariana.brocardo@sydney.edu.au.
authors.forename: Mariana G
authors.initials: MG
authors.lastname: Brocardo
authors.affiliation: Centre for Cancer Research, Westmead Institute for Medical Research, University of Sydney, Westmead, NSW 2145, Australia beric.henderson@sydney.edu.au mariana.brocardo@sydney.edu.au.
authors.forename: Beric R
authors.initials: BR
authors.lastname: Henderson
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000502:physiology / Q000648:ultrastructure*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008870:Microtubules / Q000502:physiology; D008928:Mitochondria / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009154:Mutation; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; C465341:TRAK2 protein, human; C473124:RHOT1 protein, human; D020741:rho GTP-Binding Proteins