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Excessive “excitotoxic” accumulation of Ca 2+  and Zn 2+  within neurons contributes to neurodegeneration in pathological conditions including ischemia. Putative early targets of these ions, both of which are linked to increased reactive oxygen species (ROS) generation, are mitochondria and the cytosolic enzyme, NADPH oxidase (NOX). The present study uses primary cortical neuronal cultures to examine respective contributions of mitochondria and NOX to ROS generation in response to Ca 2+  or Zn 2+  loading. Induction of rapid cytosolic accumulation of either Ca 2+  (via NMDA exposure) or Zn 2+  (via Zn 2+ /Pyrithione exposure in 0 Ca 2+ ) caused sharp cytosolic rises in these ions, as well as a strong and rapid increase in ROS generation. Inhibition of NOX activation significantly reduced the Ca 2+ -induced ROS production with little effect on the Zn 2+ - triggered ROS generation. Conversely, dissipation of the mitochondrial electrochemical gradient increased the cytosolic Ca 2+  or Zn 2+  rises caused by these exposures, consistent with inhibition of mitochondrial uptake of these ions. However, such disruption of mitochondrial function markedly suppressed the Zn 2+ -triggered ROS, while partially attenuating the Ca 2+ -triggered ROS. Furthermore, block of the mitochondrial Ca 2+  uniporter (MCU), through which Zn 2+  as well as Ca 2+  can enter the mitochondrial matrix, substantially diminished Zn 2+  triggered ROS production, suggesting that the ROS generation occurs specifically in response to Zn 2+  entry into mitochondria. Finally, in the presence of the sulfhydryl-oxidizing agent 2,2'-dithiodipyridine, which impairs Zn 2+  binding to cytosolic metalloproteins, far lower Zn 2+  exposures were able to induce mitochondrial Zn 2+  uptake and consequent ROS generation. Thus, whereas rapid acute accumulation of Zn 2+  and Ca 2+  each can trigger injurious ROS generation, Zn 2+  entry into mitochondria via the MCU may do so with particular potency. This may be of particular relevance to conditions like ischemia in which cytosolic Zn 2+  buffering is impaired due to acidosis and oxidative stress.

Mechanisms of Rapid Reactive Oxygen Species Generation in Response to Cytosolic Ca2+ or Zn2+ Loads in Cortical Neurons