title: ER-mitochondrial calcium flow underlies vulnerability of mechanosensory hair cells to damage.
abstract: Mechanosensory hair cells are vulnerable to environmental insult, resulting in hearing and balance disorders. We demonstrate that directional compartmental flow of intracellular Ca(2+) underlies death in zebrafish lateral line hair cells after exposure to aminoglycoside antibiotics, a well characterized hair cell toxin. Ca(2+) is mobilized from the ER and transferred to mitochondria via IP3 channels with little cytoplasmic leakage. Pharmacological agents that shunt ER-derived Ca(2+) directly to cytoplasm mitigate toxicity, indicating that high cytoplasmic Ca(2+) levels alone are not cytotoxic. Inhibition of the mitochondrial transition pore sensitizes hair cells to the toxic effects of aminoglycosides, contrasting with current models of excitotoxicity. Hair cells display efficient ER-mitochondrial Ca(2+) flow, suggesting that tight coupling of these organelles drives mitochondrial activity under physiological conditions at the cost of increased susceptibility to toxins.
authors.affiliation: Virginia Merrill Bloedel Hearing Research Center, Department of Otolaryngology, Head and Neck Surgery.
authors.forename: Robert
authors.initials: R
authors.lastname: Esterberg
authors.affiliation: Virginia Merrill Bloedel Hearing Research Center, Department of Biological Structure, and.
authors.forename: Dale W
authors.initials: DW
authors.lastname: Hailey
authors.affiliation: Virginia Merrill Bloedel Hearing Research Center, Department of Otolaryngology, Head and Neck Surgery, Department of Physiology and Biophysics, University of Washington, Seattle, Washington 98195 rubel@uw.edu draible@u.washington.edu.
authors.forename: Edwin W
authors.initials: EW
authors.lastname: Rubel
authors.affiliation: Virginia Merrill Bloedel Hearing Research Center, Department of Biological Structure, and rubel@uw.edu draible@u.washington.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Raible
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000494:pharmacology; D004625:Embryo, Nonmammalian; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D007814:Larva; D053403:Lateral Line System / Q000033:anatomy & histology; D008465:Mechanoreceptors / Q000187:drug effects / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics; D013997:Time Factors; D050821:Transcription Factor Brn-3C / Q000235:genetics; D015027:Zebrafish
chemical_list: D000617:Aminoglycosides; D002614:Chelating Agents; D050821:Transcription Factor Brn-3C; C089785:myosin VI; D004533:Egtazic Acid; D018995:Myosin Heavy Chains; D002118:Calcium
keywords: lateral line; zebrafish