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

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.

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