Involvement of mitochondrial K+ release and cellular efflux in ischemic and apoptotic neuronal death
Article first published online: 9 JUL 2003
Journal of Neurochemistry
Volume 86, Issue 4, pages 966–979, August 2003
How to Cite
Liu, D., Slevin, J. R., Lu, C., Chan, S. L., Hansson, M., Elmér, E. and Mattson, M. P. (2003), Involvement of mitochondrial K+ release and cellular efflux in ischemic and apoptotic neuronal death. Journal of Neurochemistry, 86: 966–979. doi: 10.1046/j.1471-4159.2003.01913.x
- Issue published online: 21 JUL 2003
- Article first published online: 9 JUL 2003
- Received March 14, 2003; revised manuscript received May 7, 2003; accepted May 12, 2003.
- cytochrome c;
We measured and manipulated intracellular potassium (K+) fluxes in cultured hippocampal neurons in an effort to understand the involvement of K+ in neuronal death under conditions of ischemia and exposure to apoptotic stimuli. Measurements of the intracellular K+ concentration using the fluorescent probe 1,3-benzenedicarboxylic acid, 4,4′-[1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diylbis(5-methoxy-6,2-benzofurandiyl)]bis-, tetrakis [(acetyloxy) methyl] ester (PBFI) revealed that exposure of neurons to cyanide (chemical hypoxia), glutamate (excitotoxic insult) or staurosporine (apoptotic stimulus) results in efflux of K+ and cell death. Treatment of neurons with 5-hydroxydecanoate (5HD), an inhibitor of mitochondrial K+ channels, reduced K+ fluxes in neurons exposed to each insult and increased the resistance of the cells to death. K+ efflux was attenuated, levels of oxyradicals were decreased, mitochondrial membrane potential was stabilized and release of cytochrome c from mitochondria was attenuated in neurons treated with 5HD. K+ was rapidly released into the cytosol from mitochondria when neurons were exposed to the K+ channel opener, diazoxide, or to the mitochondrial uncoupler, carbonyl cyanide 4(trifluoromethoxy)phenylhydrazone (FCCP), demonstrating that the intramitochondrial K+ concentration is greater than the cytosolic K+ concentration. The release of K+ from mitochondria was followed by efflux through plasma membrane K+ channels. In vivo studies showed that 5HD reduces ischemic brain damage without affecting cerebral blood flow in a mouse model of focal ischemic stroke. These findings suggest that intracellular K+ fluxes play a key role in modulating neuronal oxyradical production and cell survival under ischemic conditions, and that agents that modify K+ fluxes may have therapeutic benefit in stroke and related neurodegenerative conditions.