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      Mitochondrial Ca 2+ Uptake from Plasma Membrane Cav3.2 Protein Channels Contributes to Ischemic Toxicity in PC12 Cells*

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          Abstract

          Background: T-type Ca 2+ (Cav3.2) channel inhibitors prevent neuronal death during ischemia, but the cytotoxic signals have not been resolved.

          Results: Cav3.2 channels generate cytotoxic Ca 2+ elevations in the cytosol and mitochondria of PC12 cells deprived of oxygen and glucose.

          Conclusion: Ca 2+ transfer from Cav3.2 channels to mitochondria contributes to ischemic toxicity.

          Significance: Cav3.2 channels and the mitochondrial Ca 2+ uniporter (MCU) are potential targets for the treatment of stroke.

          Abstract

          T-type Ca 2+ channel inhibitors protect hippocampal CA1 neurons from delayed death after global ischemia in rats, suggesting that Cav3.1, Cav3.2, or Cav3.3 channels generate cytotoxic Ca 2+ elevations during anoxia. To test this hypothesis, we measured the Ca 2+ concentration changes evoked by oxygen and glucose deprivation (OGD) in the cytosol and in the mitochondria of PC12 cells. OGD evoked long-lasting cytosolic Ca 2+ elevations that were reduced by Cav3.2 inhibition (50 μ m Ni 2+) and Cav3.1/Cav3.2 silencing and potentiated by Cav3.2 overexpression. The kinetics of the sustained cytosolic Ca 2+ elevations occurring during OGD directly correlated to the extent of cell death measured 20 h after reoxygenation, which was decreased by Ni 2+ and Cav3.1/Cav3.2 silencing and increased by Cav3.2 overexpression. Ni 2+ and Cav3.1/Cav3.2 silencing delayed the decline of cellular ATP during OGD, consistent with a reduction in the Ca 2+ load actively extruded by plasma membrane Ca 2+ pumps. The cytosolic Ca 2+ elevations were paralleled by mitochondrial Ca 2+ elevations that were also increased by Cav3.2 overexpression and decreased by Ni 2+ but not by Cav3.1/Cav3.2 silencing. Overexpression and silencing of the mitochondrial Ca 2+ uniporter, the major mitochondrial Ca 2+ uptake protein, revealed that the cytotoxicity was correlated to the amplitude of the mitochondrial, rather than the cytosolic, Ca 2+ elevations. Selective activation of T-type Ca 2+ channels evoked both cytosolic and mitochondrial Ca 2+ elevations, but only the mitochondrial responses were reduced by Cav3.1/Cav3.2 silencing. We conclude that the opening of Cav3.2 channels during ischemia contribute to the entry of Ca 2+ ions that are transmitted to mitochondria, resulting in a deleterious mitochondrial Ca 2+ overload.

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          Most cited references 25

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          Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria.

          Microdomains of high intracellular calcium ion concentration, [Ca2+]i, have been hypothesized to occur in living cells exposed to stimuli that generate inositol 1,4,5-trisphosphate (IP3). Mitochondrially targeted recombinant aequorin was used to show that IP3-induced Ca2+ mobilization from intracellular stores caused increases of mitochondrial Ca2+ concentration, [Ca2+]m, the speed and amplitude of which are not accounted for by the relatively small increases in mean [Ca2+]i. A similar response was obtained by the addition of IP3 to permeabilized cells but not by perfusion of cells with Ca2+ at concentrations similar to those measured in intact cells. It is concluded that in vivo, domains of high [Ca2+]i are transiently generated close to IP3-gated channels and sensed by nearby mitochondria; this may provide an efficient mechanism for optimizing mitochondrial activity upon cell stimulation.
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            Mitochondrial transport of cations: channels, exchangers, and permeability transition.

            This review provides a selective history of how studies of mitochondrial cation transport (K+, Na+, Ca2+) developed in relation to the major themes of research in bioenergetics. It then covers in some detail specific transport pathways for these cations, and it introduces and discusses open problems about their nature and physiological function, particularly in relation to volume regulation and Ca2+ homeostasis. The review should provide the basic elements needed to understand both earlier mitochondrial literature and current problems associated with mitochondrial transport of cations and hopefully will foster new interest in the molecular definition of mitochondrial cation channels and exchangers as well as their roles in cell physiology.
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              Decoding of cytosolic calcium oscillations in the mitochondria.

              Frequency-modulated oscillations of cytosolic Ca2+ ([Ca2+]c) are believed to be important in signal transduction, but it has been difficult to correlate [Ca2+]c oscillations directly with the activity of Ca(2+)-regulated targets. We have studied the control of Ca(2+)-sensitive mitochondrial dehydrogenases (CSMDHs) by monitoring mitochondrial Ca2+ ([Ca2+]m) and the redox state of flavoproteins and pyridine nucleotides simultaneously with [Ca2+]c in single hepatocytes. Oscillations of [Ca2+]c induced by IP3-dependent hormones were efficiently transmitted to the mitochondria as [Ca2+]m oscillations. Each [Ca2+]m spike was sufficient to cause a maximal transient activation of the CSMDHs and [Ca2+]m oscillations at frequencies above 0.5 per minute caused a sustained activation of mitochondrial metabolism. By contrast, sustained [Ca2+]c increases yielded only transient CSMDH activation, and slow or partial [Ca2+]c elevations were ineffective in increasing [Ca2+]m or stimulating CSMDHs. We conclude that the mitochondria are tuned to oscillating [Ca2+]c signals, the frequency of which can control the CSMDHs over the full range of potential activities.
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                Author and article information

                Journal
                J Biol Chem
                J. Biol. Chem
                jbc
                jbc
                JBC
                The Journal of Biological Chemistry
                American Society for Biochemistry and Molecular Biology (9650 Rockville Pike, Bethesda, MD 20814, U.S.A. )
                0021-9258
                1083-351X
                3 May 2013
                18 March 2013
                18 March 2013
                : 288
                : 18
                : 12459-12468
                Affiliations
                From the Departments of []Cell Physiology and Metabolism,
                [§ ]Fundamental Neuroscience, and
                []Clinical Neurosciences, University of Geneva, Geneva CH-1211, Switzerland
                Author notes
                [1 ] To whom correspondence should be addressed: Department of Cell Physiology and Metabolism, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneva 4, Switzerland. Tel.: 41-22-379-5399; Fax: 41-22-379-5338; E-mail: Nicolas.Demaurex@ 123456unige.ch .
                Article
                M112.428128
                10.1074/jbc.M112.428128
                3642294
                23508951
                © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

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                Creative Commons Attribution Unported License applies to Author Choice Articles

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                Categories
                Cell Biology

                Biochemistry

                stroke, calcium signaling, ion channels, ischemia, mitochondria

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