Role of arachidonic acid and other free fatty acids in mitochondrial dysfunction in brain ischemia

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Abstract
The aim of the present investigation was to evaluate the possible role of arachidonic acid and other free fatty acids in ischemia-induced mitochondrial dysfunction. Respiratory activities were measured in mitochondria isolated from rat brains subjected to 15–30 min of decapitation ischemia. Addition of bovine serum albumin (BSA) to the mitochondria, isolated in BSA-free media, abolished an ischemia-induced increase in substrate-stimulated (state 4) respiration but only partly reversed a marked inhibition of substrate-, phosphate-, and ADP-stimulated (state 3) respiration caused by the ischemia. Individual free fatty acids were measured in aliquots of the same mitochondrial preparations before and after treatment with BSA. There was a significant increase in arachidonic (20:4), stearic (18:0), palmitic (16:0), and docosahexaenoic (22:6) acid during ischemia. BSA treatment removed all 20:4 and reduced the amount of 18:0 and 16:0, but had no significant effect on 22:6. The main conclusions were (1) that 20:4, 18:0, and 16.0 were responsible for the partial uncoupling (increase in state 4 respiration) of mitochondrial respiration during ischemia, (2) that the inhibition of state 3 respiration caused by ischemia could only partly be attributed to an effect of FFAs, and (3) that the ischemia-induced mitochondrial dysfunction was caused by a combination of factors including 20:4.

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