Mitochondrial Calcium Transport and Mitochondrial Dysfunction After Global Brain Ischemia in Rat Hippocampus

Abstract

Here we report effect of ischemia-reperfusion on mitochondrial Ca2+ uptake and activity of complexes I and IV in rat hippocampus. By performing 4-vessel occlusion model of global brain ischemia, we observed that 15 min ischemia led to significant decrease of mitochondrial capacity to accumulate Ca2+ to 80.8% of control whereas rate of Ca2+ uptake was not significantly changed. Reperfusion did not significantly change mitochondrial Ca2+ transport. Ischemia induced progressive inhibition of complex I, affecting final electron transfer to decylubiquinone. Minimal activity of complex I was observed 24 h after ischemia (63% of control). Inhibition of complex IV activity to 80.6% of control was observed 1 h after ischemia. To explain the discrepancy between impact of ischemia on rate of Ca2+ uptake and activities of both complexes, we performed titration experiments to study relationship between inhibition of particular complex and generation of mitochondrial transmembrane potential (DeltaPsi(m)). Generation of a threshold curves showed that complex I and IV activities must be decreased by approximately 40, and 60%, respectively, before significant decline in DeltaPsi(m) was documented. Thus, mitochondrial Ca2+ uptake was not significantly affected by ischemia-reperfusion, apparently due to excess capacity of the complexes I and IV. Inhibition of complex I is favourable of reactive oxygen species (ROS) generation. Maximal oxidative modification of membrane proteins was documented 1 h after ischemia. Although enhanced formation of ROS might contribute to neuronal injury, depressed activities of complex I and IV together with unaltered rate of Ca2+ uptake are conditions favourable of initiation of other cell degenerative pathways like opening of mitochondrial permeability transition pore or apoptosis initiation, and might represent important mechanism of ischemic damage to neurones.

Interleukin-6 reduces NMDAR-mediated cytosolic Ca2+ overload and neuronal death via JAK/CaN signaling

“…Mitochondria regulate neuronal Ca 2+ homeostasis [55]. Mitochondrial membrane potential loss, due to mitochondrial Ca 2+ accumulation, is an early event in excitotoxic neuronal death [56]. The current results that IL-6 prevented NMDA-induced mitochondrial membrane depolarization show a protection of IL-6 against early excitotoxic neuronal death.…”

Effects of NMDA-Receptor Antagonist on the Expressions of Bcl-2 and Bax in the Subventricular Zone of Neonatal Rats with Hypoxia–Ischemia Brain Damage

“…is increased, mitochondria accumulate Ca 2? , which leads to cytochrome c release from mitochondria to cytosol and activates apoptotic functions, which is an early event in excitotoxic neuronal death [22].…”

Mechanisms of Ischemic Induced Neuronal Death and Ischemic Tolerance

“…Although the values in preconditioned animals were significantly smaller compared to naive ischemia, IPC did not protect complex I from ischemia induced inhibition. On the other hand, activity of the terminal enzyme complex of respiratory chain, complex IV were slightly protected by IPC and the net effect of IPC was the shift of its minimal activity from 1 h to 3 h after reperfusion (Racay et al, 2009c).…”