title: Miro1 Regulates Activity-Driven Positioning of Mitochondria within Astrocytic Processes Apposed to Synapses to Regulate Intracellular Calcium Signaling.
abstract: It is fast emerging that maintaining mitochondrial function is important for regulating astrocyte function, although the specific mechanisms that govern astrocyte mitochondrial trafficking and positioning remain poorly understood. The mitochondrial Rho-GTPase 1 protein (Miro1) regulates mitochondrial trafficking and detachment from the microtubule transport network to control activity-dependent mitochondrial positioning in neurons. However, whether Miro proteins are important for regulating signaling-dependent mitochondrial dynamics in astrocytic processes remains unclear. Using live-cell confocal microscopy of rat organotypic hippocampal slices, we find that enhancing neuronal activity induces transient mitochondrial remodeling in astrocytes, with a concomitant, transient reduction in mitochondrial trafficking, mediated by elevations in intracellular Ca(2+). Stimulating neuronal activity also induced mitochondrial confinement within astrocytic processes in close proximity to synapses. Furthermore, we show that the Ca(2+)-sensing EF-hand domains of Miro1 are important for regulating mitochondrial trafficking in astrocytes and required for activity-driven mitochondrial confinement near synapses. Additionally, activity-dependent mitochondrial positioning by Miro1 reciprocally regulates the levels of intracellular Ca(2+) in astrocytic processes. Thus, the regulation of intracellular Ca(2+) signaling, dependent on Miro1-mediated mitochondrial positioning, could have important consequences for astrocyte Ca(2+) wave propagation, gliotransmission, and ultimately neuronal function.
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, United Kingdom.
authors.forename: Terri-Leigh
authors.initials: TL
authors.lastname: Stephen
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, United Kingdom.
authors.forename: Nathalie F
authors.initials: NF
authors.lastname: Higgs
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, United Kingdom.
authors.forename: David F
authors.initials: DF
authors.lastname: Sheehan
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, United Kingdom.
authors.forename: Sana
authors.initials: S
authors.lastname: Al Awabdh
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, United Kingdom.
authors.forename: Guillermo
authors.initials: G
authors.lastname: López-Doménech
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, United Kingdom.
authors.forename: I Lorena
authors.initials: IL
authors.lastname: Arancibia-Carcamo
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, United Kingdom j.kittler@ucl.ac.uk.
authors.forename: Josef T
authors.initials: JT
authors.lastname: Kittler
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000648:ultrastructure*; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics; D004622:Embryo, Mammalian; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D042541:Intracellular Space / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D009924:Organ Culture Techniques; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000502:physiology*; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018683:Excitatory Amino Acid Agents; D005904:Glial Fibrillary Acidic Protein; D024101:Mitochondrial Proteins; D050598:Vesicular Glutamate Transport Protein 1; D018698:Glutamic Acid; C540072:Rhot1 protein, rat; D020741:rho GTP-Binding Proteins
keywords: Miro; NMDARs; astrocyte; calcium; mitochondria; mobility