Zn entry through the mitochondrial calcium uniporter is a critical contributor to mitochondrial dysfunction and neurodegeneration.

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2019
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Abstract
Excitotoxic Ca accumulation contributes to ischemic neurodegeneration, and Ca can enter the mitochondria through the mitochondrial calcium uniporter (MCU) to promote mitochondrial dysfunction. Yet, Ca-targeted therapies have met limited success. A growing body of evidence has highlighted the underappreciated importance of Zn, which also accumulates in neurons after ischemia and can induce mitochondrial dysfunction and cell death. While studies have indicated that Zn can also enter the mitochondria through the MCU, the specificity of the pore's role in Zn-triggered injury is still debated. Present studies use recently available MCU knockout mice to examine how the deletion of this channel impacts deleterious effects of cytosolic Zn loading. In cultured cortical neurons from MCU knockout mice, we find significantly reduced mitochondrial Zn accumulation. Correspondingly, these neurons were protected from both acute and delayed Zn-triggered mitochondrial dysfunction, including mitochondrial reactive oxygen species generation, depolarization, swelling and inhibition of respiration. Furthermore, when toxic extramitochondrial effects of Ca entry were moderated, both cultured neurons (exposed to Zn) and CA1 neurons of hippocampal slices (subjected to prolonged oxygen glucose deprivation to model ischemia) from MCU knockout mice displayed decreased neurodegeneration. Finally, to examine the therapeutic applicability of these findings, we added an MCU blocker after toxic Zn exposure in wildtype neurons (to induce post-insult MCU blockade). This significantly attenuated the delayed evolution of both mitochondrial dysfunction and neurotoxicity. These data-combining both genetic and pharmacologic tools-support the hypothesis that Zn entry through the MCU is a critical contributor to ischemic neurodegeneration that could be targeted for neuroprotection.
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ji2019znexperimental Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Ji, Sung G;Medvedeva, Yuliya V;Weiss, John H;
Journal experimental neurology
Year 2019
DOI S0014-4886(19)30308-5
URL
Keywords
Zinc reactive oxygen species neuroprotection mitochondria ischemia neurodegeneration cell death calcium excitotoxicity hippocampal slice mitochondrial calcium uniporter neuronal cultures vscc

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