Bs. Kristal et Jm. Dubinsky, MITOCHONDRIAL PERMEABILITY TRANSITION IN THE CENTRAL-NERVOUS-SYSTEM -INDUCTION BY CALCIUM CYCLING-DEPENDENT AND CYCLING-INDEPENDENT PATHWAYS, Journal of neurochemistry, 69(2), 1997, pp. 524-538
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.