This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. EM tomography revealed a striking remodeling of mitochondria following exposure to zinc (Zn2+) and nitric oxide (NO). Nitric oxide and Zn2+ are implicated in the pathogenesis of cerebral ischemia and other neurodegenerative diseases. However, the relationship and the molecular basis of their neurotoxic effects were unclear when we started this collaboration. Recently, we showed that nitric oxide/peroxynitrite (NO/ONOO-) leads to liberation of Zn2+ from intracellular stores in primary cortical neurons. Similarly, pathophysiological stimuli, like N-methyl-D-aspartate receptor overactivation, resulted in increased free intracellular Zn2+ levels. Free Zn2+, in turn, impinges on mitochondrial function inducing respiratory block, cytochrome c release, generation of reactive oxygen species, and p38 MAP kinase activation. In addition, Zn2+, similar to Ca2+, induced mitochondrial swelling detected by electron microscope tomography. Additionally, time-lapse microscopy revealed that this pathway lead to rapid caspase-independent K+ efflux with concomitant cell shrinkage; patch-clamp recording showed that activation of voltage-gated K+ channels underlies this K+ efflux. Importantly, Zn2+ chelators, ROS scavengers, Bcl-xL overexpression, dominant-negative p38, or K+ channel inhibitors all delayed NO-induced K+ efflux, cell volume loss, and neuronal apoptosis. Thus, these results suggest a previously unknown crosstalk between NO and Zn2+ apoptotic signaling pathways that may contribute the pathogenesis of neurodegeneration
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