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GTPase dependent recruitment of Grif-1 by Miro1 regulates mitochondrial trafficking in hippocampal neurons
Authors:Andrew F. MacAskill  Kieran Brickley  F. Anne Stephenson  Josef T. Kittler
Affiliation:1. Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK;2. School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1N 1AX, UK;1. Department of Biosciences, Università degli Studi di Milano, Milano, Italy;2. Department of Physiology, Keio University School of Medicine, Tokyo, Japan;3. Division of Neuroscience, San Raffaele Scientific Institute and Vita-Salute University, Milano, Italy;4. Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Cusano Milanino, MI, Italy;5. Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan;6. Parkinson Institute, ASST G.Pini-CTO, ex ICP, Milano, Italy;7. Stem Cell laboratory for CNS Disease Modeling, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, BMC A10, Lund, Sweden;8. Strategic Research Area MultiPark and Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, Lund, Sweden;9. Center of Excellence of Neurodegenerative Diseases, Università degli Studi di Milano, Milano, Italy;1. Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK;3. From the Department of Neuroscience, Physiology, and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom,;5. the Neuroscience Research Unit, Pfizer, Cambridge, Massachusetts 02139;4. the Department of Neuropathology, Heinrich Heine University, Moorenstrasse 5, 40225 Dusseldorf, Germany;1. Heart and Vascular Institute, Department of Medicine, Department of Cellular and Molecular Physiology, Pennsylvania State University, College of Medicine, Hershey, PA, USA;2. Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA;3. Department of Microbiology, Bharathidasan University, Tiruchirapalli, Tamil Nadu, India
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.
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