MITOCHONDRIAL PERMEABILITY TRANSITION IN THE CENTRAL-NERVOUS-SYSTEM -INDUCTION BY CALCIUM CYCLING-DEPENDENT AND CYCLING-INDEPENDENT PATHWAYS

Isolated rat CNS mitochondria and cultured cortical astrocytes were ex amined for behavior indicative of a mitochondrial permeability transit ion (mPT). Exposure of isolated CNS mitochondria to elevated calcium o r phosphate or both produced loss of absorbance indicative of mitochon drial swelling. The absorbance decreases were prevented by ADP and Mg2 + and reduced by cyclosporin A, dithiothreitol, and N-ethylmaleimide. Ruthenium red prevented calcium cycling-induced, but only attenuated p hosphate-induced losses of absorbance. In cultured astrocytes permeabi lized with digitonin or treated with the calcium ionophore, 4-bromo-A2 3187, elevations of external calcium altered mitochondrial morphology visualized with the dye, JC-1, from rod-like to rounded, swollen struc tures. Similar changes were observed in digitonin-permeabilized astroc ytes exposed to phosphate. The incidence of calcium-induced changes in astrocyte mitochondria was prevented by Mg2+ and pretreatment with di thiothreitol and N-ethylmaleimide, and was reduced by cyclosporin A, A DP, and butacaine alone or in combinations. Ruthenium red and the Na+/ Ca2+ exchange inhibitor CGP 37157 blocked calcium cycling and prevente d mitochondrial shape changes in digitonin-treated, but not ionophore- treated astrocytes. Thus, the demonstrated induction conditions and ph armacological profile indicated the existence of an mPT in brain mitoc hondria. The mPT occurred consequent to activation of calcium cycling- dependent and -independent pathways. Induction of an mPT could contrib ute to neuronal injury following ischemia and reperfusion.