Selective Reductions in the Activity of the Pyruvate Dehydrogenase Complex in Mitochondria Isolated from Brain Subregions following Forebrain Ischemia in Rats

Abstract

Previous studies showed that in rats exposed to 30 min of forebrain ischemia, there were reductions in pyruvate-supported respiration within the first 3 h of recirculation in mitochondria isolated from the dorsolateral striatum (a region in which the majority of neurons are susceptible to ischemia) but not the ischemia-resistant paramedian neocortex. The present study demonstrates that the changes in mitochondrial respiration apparently result from a loss of activity of the pyruvate dehydrogenase complex (PDHC). In mitochondria from the dorsolateral striatum, incubated in the presence of pyruvate and ADP (state 3 conditions) and treated to preserve the phosphorylation state of PDHC, there was no significant change from preischemic activity after 30 min of ischemia or 1 h of recirculation. However, a significant reduction (to 71% of control value) was observed at 3 h of recirculation, and the activity decreased further at 6 and 24 h (to 64 and 43% of control values, respectively). Total PDHC activity in the isolated mitochondria was similarly reduced at 3 h (68% of control values) and 6 h (73% of control values), indicating that the alteration was due to loss or inactivation of the PDHC rather than changes in phosphorylation of the complex. No significant changes were observed in the activity of two other mitochondrial markers, rotenone-sensitive NADH-cytochrome c oxidoreductase and α-ketoglutarate dehydrogenase. None of the activities of these three enzymes in mitochondria from the paramedian neocortex was significantly affected by ischemia or recirculation. These results (together with previous observations) indicate an early and specific change affecting the PDHC in cells of the dorsolateral striatum. This change occurs sufficiently early that it could contribute to the degenerative process in affected cells. At a minimum, the change in PDHC provides an early marker for degeneration in the dorsolateral striatum.