Crosstalk between Nitric Oxide and Zinc Pathways to Neuronal Cell Death Involving Mitochondrial Dysfunction and p38-Activated K+ Channels

Abstract

Nitric oxide (NO) and zinc (Zn2+) are implicated in the pathogenesis of cerebral ischemia and neurodegenerative diseases. However, their relationship and the molecular mechanism of their neurotoxic effects remain unclear. Here we show that addition of exogenous NO or NMDA (to increase endogenous NO) leads to peroxynitrite (ONOO-) formation and consequent Zn2+ release from intracellular stores in cerebrocortical neurons. Free Zn2+ in turn induces respiratory block, mitochondrial permeability transition (mPT), cytochrome c release, generation of reactive oxygen species (ROS), and p38 MAP kinase activation. This pathway leads to caspase-independent K+ efflux with cell volume loss and apoptotic-like death. Moreover, Zn2+ chelators, ROS scavengers, Bcl-xL, dominant-interfering p38, or K+ channel blockers all attenuate NO-induced K+ efflux, cell volume loss, and neuronal apoptosis. Thus, these data establish a new form of crosstalk between NO and Zn2+ apoptotic signal transduction pathways that may contribute to neurodegeneration.

Sequential Release of Nitric Oxide, Zinc, and Superoxide in Hypoglycemic Neuronal Death

“…Reactive oxygen species produced by NADPH oxidase lead to increased zinc accumulation, PARP-1 activation, and resultant cell death. Undoubtedly, this sequence is not entirely linear, and earlier work suggests that crosstalk between these events is likely (Bossy-Wetzel et al, 2004). In addition, this sequence does not exclude other contributory mechanisms, particularly in regions of brain where there is less concentration of zinc compared with hippocampus.…”

Cerium oxide nanoparticles protect against Aβ-induced mitochondrial fragmentation and neuronal cell death

“…Fluorescence microscopy was performed as previously described. 11 Quantification of fluorescence from 3-NT was as follows. Exposure time, brightness and contrast of randomly selected cortical neurons were held constant for all images within same experiment.…”

“…8,9 Moreover, peroxynitrite can trigger the release of free metals such as Zn 2 þ from intracellular stores with consequent inhibition of mitochondrial function and enhancement of neuronal cell death. [10][11][12] Finally, peroxynitrite can irreversibly inhibit complexes I and IV of the mitochondrial respiratory chain. 11,13 Because mitochondria have a critical role in neurons as energy producers to fuel vital processes such as synaptic transmission and axonal transport, 14 and mitochondrial dysfunction is a well-documented and early event in AD, 15 it is important to consider how peroxynitrite and nitrosative stress affect mitochondria.…”

“…[10][11][12] Finally, peroxynitrite can irreversibly inhibit complexes I and IV of the mitochondrial respiratory chain. 11,13 Because mitochondria have a critical role in neurons as energy producers to fuel vital processes such as synaptic transmission and axonal transport, 14 and mitochondrial dysfunction is a well-documented and early event in AD, 15 it is important to consider how peroxynitrite and nitrosative stress affect mitochondria. Although the ultimate cause of mitochondrial dysfunction in AD remains unclear, an imbalance in mitochondrial fission and fusion is one possibility.…”

Apoptotic surface delivery of K+ channels

“…3 The potassium current enhancement, which is protein synthesis independent and precedes caspase activation, 4 can be triggered by classical apoptotic stimuli like staurosporine, 3 serum withdrawal, 3 and amyloid b, 5 or by oxidants such as 2,2 0 -dithiodipyridine (DTDP) 4,6 and peroxynitrite. 7,8 In oxidant-induced neuronal apoptosis, the enhancement of K þ currents is dependent upon the liberation of intracellular Zn 2 þ from metal-containing proteins 6,7 and requires the activation of the mitogen-activated protein kinase (MAPK) pathway involving apoptosis signal-regulating kinase-1 8 and p38. 9 We previously demonstrated that Kv2.1-encoded potassium channels mediate the enhanced K þ currents observed in cortical neuron apoptosis.…”