Differences in the activation of the mitochondrial permeability transitionamong brain regions in the rat correlate with selective vulnerability

Mitochondria from different regions of the brain were prepared, and the act ivation of the mitochondrial permeability transition (MPT) by calcium was i nvestigated by monitoring the associated mitochondrial swelling. In general , the properties of the MPT in brain mitochondria were found to be qualitat ively similar to those observed in liver and heart mitochondria. Thus, swel ling was inhibited by adenine nucleotides (AdNs) and low pH (<7.0), whereas thiol reagents and alkalosis facilitated swelling. Cyclosporin A and its n onimmunosuppressive analogue N-methyl-Val-4-cyclosporin A (PKF 220-384) bot h inhibited swelling and prevented the translocation of cyclophilin D from the matrix to the membranes of cortical mitochondria. However, the calcium sensitivity of the MPT differed in mitochondria from three brain regions (h ippocampus > cortex > cerebellum) and is correlated with the susceptibility of these regions to ischemic damage. Depleting mitochondria of AdNs by tre atment with pyrophosphate ions sensitized the MPT to [Ca2+] and abolished r egional differences, implying regional differences in mitochondrial AdN con tent. This was confirmed by measurements showing significant differences in AdN content among regions (cerebellum > cortex > hippocampus). Our data ad d td recent evidence that the MPT may be involved in neuronal death.