title: Kinesin-1-syntaphilin coupling mediates activity-dependent regulation of axonal mitochondrial transport.
abstract: Axonal mitochondria are recruited to synaptic terminals in response to neuronal activity, but the mechanisms underlying activity-dependent regulation of mitochondrial transport are largely unknown. In this paper, using genetic mouse model combined with live imaging, we demonstrate that syntaphilin (SNPH) mediates the activity-dependent immobilization of axonal mitochondria through binding to KIF5. In vitro analysis showed that the KIF5-SNPH coupling inhibited the motor adenosine triphosphatase. Neuronal activity further recruited SNPH to axonal mitochondria. This motor-docking interplay was induced by Ca(2+) and synaptic activity and was necessary to establish an appropriate balance between motile and stationary axonal mitochondria. Deleting snph abolished the activity-dependent immobilization of axonal mitochondria. We propose an "Engine-Switch and Brake" model, in which SNPH acts both as an engine off switch by sensing mitochondrial Rho guanosine triphosphatase-Ca(2+) and as a brake by anchoring mitochondria to the microtubule track. Altogether, our study provides new mechanistic insight into the molecular interplay between motor and docking proteins, which arrests axonal mitochondrial transport in response to changes in neuronal activity.
authors.affiliation: Synaptic Function Section, The Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Chen
authors.forename: Zu-Hang
authors.initials: ZH
authors.lastname: Sheng
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D001692:Biological Transport; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D009435:Synaptic Transmission; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C507512:Kif5A protein, mouse; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C573782:Miro-1 protein, mouse; D009419:Nerve Tissue Proteins; C527531:Snph protein, mouse; C573783:TRAK2 protein, mouse; D016547:Kinesins; D020741:rho GTP-Binding Proteins; D002118:Calcium