Zn2+ entry through the mitochondrial calcium uniporter is a critical contributor to mitochondrial dysfunction and neurodegeneration

• Published in: Experimental neurology 2020-03, Vol.325, p.113161-113161, Article 113161
• Main Authors: Ji, Sung G., Medvedeva, Yuliya V., Weiss, John H.
• Format: Article
• Language: English
• Subjects: Calcium; Cell death; Excitotoxicity; Hippocampal slice; Ischemia; Mitochondria; Mitochondrial calcium uniporter; Neurodegeneration; Neuronal cultures; Neuroprotection; Reactive oxygen species; VSCC; Zinc
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2019.113161

Excitotoxic Ca2+ accumulation contributes to ischemic neurodegeneration, and Ca2+ can enter the mitochondria through the mitochondrial calcium uniporter (MCU) to promote mitochondrial dysfunction. Yet, Ca2+-targeted therapies have met limited success. A growing body of evidence has highlighted the underappreciated importance of Zn2+, which also accumulates in neurons after ischemia and can induce mitochondrial dysfunction and cell death. While studies have indicated that Zn2+ can also enter the mitochondria through the MCU, the specificity of the pore's role in Zn2+-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 Zn2+ loading. In cultured cortical neurons from MCU knockout mice, we find significantly reduced mitochondrial Zn2+ accumulation. Correspondingly, these neurons were protected from both acute and delayed Zn2+-triggered mitochondrial dysfunction, including mitochondrial reactive oxygen species generation, depolarization, swelling and inhibition of respiration. Furthermore, when toxic extramitochondrial effects of Ca2+ entry were moderated, both cultured neurons (exposed to Zn2+) 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 Zn2+ 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 Zn2+ entry through the MCU is a critical contributor to ischemic neurodegeneration that could be targeted for neuroprotection. •Zn2+ thought to enter the mitochondria via the mitochondrial Ca2+ uniporter (MCU)•Mitochondrial Zn2+ loading and its consequences are attenuated in MCU knockout mice.•Zn2+ contributions to neurodegeneration are attenuated in MCU knockout.•Delayed MCU blockade attenuates mitochondrial dysfunction and neurotoxicity.•Targeting mitochondrial Zn2+ through the MCU may offer significant neuroprotection.