title: GTPase dependent recruitment of Grif-1 by Miro1 regulates mitochondrial trafficking in hippocampal neurons.
abstract: The transport of mitochondria to specific neuronal locations is critical to meet local cellular energy demands and for buffering intracellular calcium. A critical role for kinesin motor proteins in mitochondrial transport in neurons has been demonstrated. Currently however the molecular mechanisms that underlie the recruitment of motor proteins to mitochondria, and how this recruitment is regulated remain unclear. Here we show that a protein trafficking complex comprising the adaptor protein Grif-1 and the atypical GTPase Miro1 can be detected in mammalian brain where it is localised to neuronal mitochondria. Increasing Miro1 expression levels recruits Grif-1 to mitochondria. This results in an enhanced transport of mitochondria towards the distal ends of neuronal processes. Uncoupling Grif-1 recruitment to mitochondria by expressing a Grif-1/Miro1 binding fragment dramatically reduces mitochondrial transport into neuronal processes. Altering Miro1 function by mutating its first GTPase domain affects Miro's ability to recruit Grif-1 to mitochondria and in addition alters mitochondrial distribution and shape along neuronal processes. These data suggest that Miro1 and the kinesin adaptor Grif-1 play an important role in regulating mitochondrial transport in neurons.
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, UK.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: MacAskill
authors.forename: Kieran
authors.initials: K
authors.lastname: Brickley
authors.forename: F Anne
authors.initials: FA
authors.lastname: Stephenson
authors.forename: Josef T
authors.initials: JT
authors.lastname: Kittler
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D026901:Membrane Transport Proteins; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D020409:Molecular Motor Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; D020409:Molecular Motor Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; C489998:Tomm20 protein, rat; C517505:Trak2 protein, rat; D020558:GTP Phosphohydrolases; C473124:RHOT1 protein, human; C540072:Rhot1 protein, rat; D020741:rho GTP-Binding Proteins