title: The interactive roles of zinc and calcium in mitochondrial dysfunction and neurodegeneration.
abstract: Zinc has been implicated in neurodegeneration following ischemia. In analogy with calcium, zinc has been proposed to induce toxicity via mitochondrial dysfunction, but the relative role of each cation in mitochondrial damage remains unclear. Here, we report that under conditions mimicking ischemia in hippocampal neurons - normal (2 mM) calcium plus elevated (> 100 μM) exogenous zinc - mitochondrial dysfunction evoked by glutamate, kainate or direct depolarization is, despite significant zinc uptake, primarily governed by calcium. Thus, robust mitochondrial ion accumulation, swelling, depolarization, and reactive oxygen species generation were only observed after toxic stimulation in calcium-containing media. This contrasts with the lack of any mitochondrial response in zinc-containing but calcium-free medium, even though zinc uptake and toxicity were strong under these conditions. Indeed, abnormally high, ionophore-induced zinc uptake was necessary to elicit any mitochondrial depolarization. In calcium- and zinc-containing media, depolarization-induced zinc uptake facilitated cell death and enhanced accumulation of mitochondrial calcium, which localized to characteristic matrix precipitates. Some of these contained detectable amounts of zinc. Together these data indicate that zinc uptake is generally insufficient to trigger mitochondrial dysfunction, so that mechanism(s) of zinc toxicity must be different from that of calcium.
authors.affiliation: Laboratory of Neurobiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Natalia B
authors.initials: NB
authors.lastname: Pivovarova
authors.forename: Ruslan I
authors.initials: RI
authors.lastname: Stanika
authors.forename: Galina
authors.initials: G
authors.lastname: Kazanina
authors.forename: Idalis
authors.initials: I
authors.lastname: Villanueva
authors.forename: S Brian
authors.initials: SB
authors.lastname: Andrews
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000473:pathology; D002118:Calcium / Q000494:pharmacology / Q000502:physiology* / Q000633:toxicity; D015220:Calcium Channels / Q000502:physiology; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004577:Electron Probe Microanalysis; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D007202:Indicators and Reagents; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D028361:Mitochondrial Diseases / Q000378:metabolism / Q000503:physiopathology*; D008933:Mitochondrial Swelling / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000503:physiopathology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D018091:Receptors, AMPA / Q000502:physiology; D015032:Zinc / Q000494:pharmacology / Q000502:physiology* / Q000633:toxicity
chemical_list: D015220:Calcium Channels; D007202:Indicators and Reagents; D017382:Reactive Oxygen Species; D018091:Receptors, AMPA; D015032:Zinc; D002118:Calcium
keywords: cell death; electron microscopy; excitotoxicity; hippocampal neurons; ischemia