title: Transient Opening of the Mitochondrial Permeability Transition Pore Induces Microdomain Calcium Transients in Astrocyte Processes.
abstract: Astrocytes extend highly branched processes that form functionally isolated microdomains, facilitating local homeostasis by redistributing ions, removing neurotransmitters, and releasing factors to influence blood flow and neuronal activity. Microdomains exhibit spontaneous increases in calcium (Ca2+), but the mechanisms and functional significance of this localized signaling are unknown. By developing conditional, membrane-anchored GCaMP3 mice, we found that microdomain activity that occurs in the absence of inositol triphosphate (IP3)-dependent release from endoplasmic reticulum arises through Ca2+efflux from mitochondria during brief openings of the mitochondrial permeability transition pore. These microdomain Ca2+transients were facilitated by the production of reactive oxygen species during oxidative phosphorylation and were enhanced by expression of a mutant form of superoxide dismutase 1 (SOD1 G93A) that causes astrocyte dysfunction and neurodegeneration in amyotrophic lateral sclerosis (ALS). By localizing mitochondria to microdomains, astrocytes ensure local metabolic support for energetically demanding processes and enable coupling between metabolic demand and Ca2+signaling events.
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Pei-Hsun
authors.initials: PH
authors.lastname: Wu
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Ethan G
authors.initials: EG
authors.lastname: Hughes
authors.affiliation: Department of Anatomy, Kitasato University School of Medicine, Sagamihara 252-0374, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukaya
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Max A
authors.initials: MA
authors.lastname: Tischfield
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Abraham J
authors.initials: AJ
authors.lastname: Langseth
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Denis
authors.initials: D
authors.lastname: Wirtz
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: dbergles@jhmi.edu.
authors.forename: Dwight E
authors.initials: DE
authors.lastname: Bergles
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D010085:Oxidative Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D000072105:Superoxide Dismutase-1 / Q000235:genetics
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D015544:Inositol 1,4,5-Trisphosphate; D000072105:Superoxide Dismutase-1; D002118:Calcium
keywords: ATP; astrocyte; calcium; cortex; in vivo; metabolism; microdomain; mitochondria; two-photon