Regulation of the Ca-independent phospholipase A2 in liver mitochondria by changes in the energetic state

The effect of electron transport chain redox status on activity of the mitochondrial Ca²⁺-independent phospholipase A₂ (iPLA₂) has been examined. When oxidizing NAD-linked substrates, the enzyme is not active unless deenergization occurs. Uncoupler, rotenone, antimycin A, and cyanide are equally effective at upregulating the enzyme, while oligomycin is ineffective. Thenoyltrifluoroacetone causes deenergization and activates the enzyme, but only if succinate is the respiratory substrate. These findings show that the mitochondrial iPLA₂ responds to the energetic state overall, rather than to the redox status of individual electron transport chain complexes. With NAD-linked substrates, and using rotenone to deenergize, iPLA₂ activation can be reversed by adding succinate to reestablish a membrane potential. For this purpose, ascorbate plus N,N,N′N′-tetramethyl-phenylenediamine can be used instead of succinate and is equally effective. With succinate as substrate, the membrane potential can be reduced in a graded and stable fashion by adding increasing concentrations of malonate, which is a competitive inhibitor of succinate utilization. A partial and stable activation of the iPLA₂ accompanies partial deenergization. These findings suggest that in addition to the several functions that have been proposed, the mitochondrial iPLA₂ may help to coordinate local capillary blood flow with changing energy demands.