Lanthanum suppresses arachidonic acid-induced cell death and mitochondrial depolarization in PC12 cells.
Within the framework of studying the mechanisms of acute toxicity of arachidonic acid and the role of ambient cations, we have investigated the effects of extracellular La(3+) on arachidonic acid-induced death (lactate dehydrogenase release) and mitochondrial depolarization (rhodamine 123 fluorescence) in PC12 cells. Micromolar La(3+) profoundly suppressed arachidonic acid toxicity and this effect was dependent on the presence of other cations. Whereas in the cation-free solution 10-20 microM La(3+) protected most cells from death caused by a 2 hour-long exposure to 20 microM arachidonic acid, the cytoprotective effect of 100 microM La(3+) was reduced to approximately 70% in the presence of a normal complement of monovalent cations and was hardly detectable with 5 mM Ca(2+) in the bath. Increasing the concentration of arachidonic acid could defeat La(3+) cytoprotection. In fluorescence experiments, arachidonic acid caused a decrease in the mitochondrial membrane potential, with the rate and extent of depolarization increasing with an increase in the concentration of arachidonic acid. La(3+) countered the depolarizing effect of arachidonic acid in a manner consistent with a decrease in the effective arachidonic acid concentration. The results suggest that extracellular cations modulate cellular effects of arachidonic acid by reducing its ability to pass through the plasma membrane, possibly by binding the fatty acid. The similarities of the La(3+) effects on arachidonic acid-induced cell death and arachidonic acid-induced mitochondrial depolarization strongly support the causal relations between the two events and suggest that mitochondria are the primary target of arachidonic acid at the cellular level.
Doroshenko
Nina
N
Ottawa Health Research Institute, Ottawa, Ontario, Canada K1Y 4E9.
Doroshenko
Petro
P
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism* / Q000633:toxicity; D002118:Calcium / Q000378:metabolism; D002412:Cations; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D019610:Cytoprotection; D005110:Extracellular Space / Q000378:metabolism; D007811:Lanthanum / Q000378:metabolism / Q000494:pharmacology*; D008564:Membrane Potentials; D008928:Mitochondria / Q000502:physiology; D016716:PC12 Cells; D051381:Rats
D002412:Cations; D016718:Arachidonic Acid; D007811:Lanthanum; D002118:Calcium