Induction of permeability transition and swelling of rat brain mitochondria by glutamine

Exposure of rat cerebral mitochondria to 2-10 mM glutamine (Gln) for 20 min , produced a concentration-dependent, gradual decrease of light scattering reflecting mitochondrial swelling. The light scattering decreasing effect o f 5 mM Gln was attenuated by 0.5 mu M cyclosporin A (CsA), an inhibitor of mitochondrial permeability transition (mPT) induction. Histidine (His), whi ch is a potent inhibitor of high affinity Gln uptake to mitochondria, atten uated Gln-induced decrease of mitochondrial light scattering when added at equimolar concentration, and abolished the decrease when added at 15 mM con centration shortly before addition of Gln. His inhibited the uptake of 5 mM [C-14]Gln in a concentration-dependent manner as measured during 3 min inc ubation. CsA did neither affect [C-14]Gln uptake nor modified its inhibitio n by His. The effects of 5 mM His and 0.5 mu M CsA on mitochondrial light s cattering were additive, indicating that mitochondrial swelling represents a cummulative effect of Gln -driven entry of osmotically obligated water an d induction of mPT. Addition of ammonium ions at neurotoxic concentrations neither influenced the decrease of light scattering induced by Gln, nor pro duced any change in light scattering when added alone. The results point to mitochondrial swelling and subsequent activation of mPT, as one of the pot ential mechanisms by which Gln induces metabolic disturbances in the brain in hyperammonemic conditions. (C) 2000 Intox Press, Inc.