title: Mitochondria modulate the spatio-temporal properties of intra- and intercellular Ca2+ signals in cochlear supporting cells.
abstract: In the cochlea, cell damage triggers intercellular Ca2+ waves that propagate through the glial-like supporting cells that surround receptor hair cells. These Ca2+ waves are thought to convey information about sensory hair cell-damage to the surrounding supporting cells within the cochlear epithelium. Mitochondria are key regulators of cytoplasmic Ca2+ concentration ([Ca2+](cyt)), and yet little is known about their role during the propagation of such intercellular Ca2+ signalling. Using neonatal rat cochlear explants and fluorescence imaging techniques, we explore how mitochondria modulate supporting cell [Ca2+](cyt) signals that are triggered by ATP or by hair cell damage. ATP application (0.1-50 microM) caused a dose dependent increase in [Ca2+](cyt) which was accompanied by an increase in mitochondrial calcium. Blocking mitochondrial Ca2+ uptake by dissipating the mitochondrial membrane potential using CCCP and oligomycin or using Ru360, an inhibitor of the mitochondrial Ca2+ uniporter, enhanced the peak amplitude and duration of ATP-induced [Ca2+](cyt) transients. In the presence of Ru360, the mean propagation velocity, amplitude and extent of spread of damage-induced intercellular Ca2+ waves was significantly increased. Thus, mitochondria function as spatial Ca2+ buffers during agonist-evoked [Ca2+](cyt) signalling in cochlear supporting cells and play a significant role in regulating the spatio-temporal properties of intercellular Ca2+ waves.
authors.affiliation: UCL Ear Institute, 332 Gray's Inn Road, London WC1X 8EE, UK; Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Zoë F
authors.initials: ZF
authors.lastname: Mann
authors.forename: Michael R
authors.initials: MR
authors.lastname: Duchen
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Gale
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002450:Cell Communication; D016923:Cell Death; D002478:Cells, Cultured; D003051:Cochlea / Q000166:cytology; D006198:Hair Cells, Auditory / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017136:Ion Transport / Q000187:drug effects; D007476:Ionophores / Q000494:pharmacology; D007760:Labyrinth Supporting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009840:Oligomycins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017975:Ruthenium Compounds / Q000494:pharmacology
chemical_list: D007476:Ionophores; D009840:Oligomycins; C112020:Ru 360; D017975:Ruthenium Compounds; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D000255:Adenosine Triphosphate; D002118:Calcium