Nitric oxide kills hepatocytes by mobilizing mitochondrial calcium.
We have recently shown (Schweizer, M., and Richter, C. (1994) Biochem. Biophys. Res. Commun. 204, 169-175) that nitric oxide (nitrogen monoxide, NO) at low concentrations potently and reversibly deenergizes isolated liver and brain mitochondria at oxygen concentrations that prevail in cells and tissues. We now report that also in freshly prepared hepatocytes NO deenergizes mitochondria. Deenergization is reversible at low, but longer-lasting at higher NO concentrations. The drop and the recovery of the mitochondrial membrane potential are accompanied by a rise and fall of cytosolic Ca2+ levels. At higher concentrations NO kills hepatocytes. Killing is reduced when the cytosolic Ca2+ is chelated, or when the cyclic uptake and release of Ca2+ ("Ca2+ cycling") by mitochondria is prevented. We conclude that NO can kill cells by deenergizing mitochondria and thereby flooding the cytosol with Ca2+.
Richter
C
C
Laboratory of Biochemistry I, Swiss Federal Institute of Technology, Zürich.
Gogvadze
V
V
Schlapbach
R
R
Schweizer
M
M
Schlegel
J
J
D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology; D007425:Intracellular Membranes / Q000502:physiology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018613:Microscopy, Confocal; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000633:toxicity*; D051381:Rats
D009569:Nitric Oxide; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D000968:Antimycin A; D002118:Calcium; D004229:Dithiothreitol