Role of calcium signaling in the activation of mitochondrial nitric oxide synthase and citric acid cycle

Abstract

An apparent discrepancy arises about the role of calcium on the rates of oxygen consumption by mitochondria: mitochondrial calcium increases the rate of oxygen consumption because of the activation of calcium-activated dehydrogenases, and by activating mitochondrial nitric oxide synthase (mtNOS), decreases the rates of oxygen consumption because nitric oxide is a competitive inhibitor of cytochrome oxidase. To this end, the rates of oxygen consumption and nitric oxide production were followed in isolated rat liver mitochondria in the presence of either L-Arg (to sustain a mtNOS activity) or N(G)-monomethyl-L-Arg (NMMA, a competitive inhibitor of mtNOS) under State 3 conditions. In the presence of NMMA, the rates of State 3 oxygen consumption exhibited a K(0.5) of 0.16 microM intramitochondrial free calcium, agreeing with those required for the activation of the Krebs cycle. By plotting the difference between the rates of oxygen consumption in State 3 with L-Arg and with NMMA at various calcium concentrations, a K(0.5) of 1.2 microM intramitochondrial free calcium was obtained, similar to the K(0.5) (0.9 microM) of the dependence of the rate of nitric oxide production on calcium concentrations. The activation of dehydrogenases, followed by the activation of mtNOS, would lead to the modulation of the Krebs cycle activity by the modulation of nitric oxide on the respiratory rates. This would ensue in changes in the NADH/NAD and ATP/ADP ratios, which would influence the rate of the cycle and the oxygen diffusion.

CO2 and HCO3- Permeability of the Rat Liver Mitochondrial Membrane

“…The oxygen consumption (state III) was 97 (SD ± 38; n = 28) nmol O 2 /min/mg protein and the RCR was around 10 (SD ± 5; n = 8). State three respiration rates and RCR values were in the range of literature values for liver mitochondria [10,13,17,18]. In transmission electron microscopy, the mitochondria appeared morphologically intact and little other material was seen (Fig.…”

Changes in mitochondrial functionality and calcium uptake in hypertensive rats as a function of age

“…NO • is a free radical that binds to cytochrome c oxidase (complex IV) of the mitochondrial electron transport chain to inhibit respiration by competitive action with oxygen in complex IV, and therefore regulates the membrane potential (ΔΨ) and ATP synthesis (Giulivi et al, 1998;Ghafourifar and Richter, 1999;Aguilera-Aguirre et al, 2002;Calderón-Cortés et al, 2006). mtNOS and the enzymes mentioned above regulate ATP synthesis to support cellular energetic requirements (Bringold et al, 2000;Traaseth et al, 2004).…”

Increased Abdominal Adiposity Exacerbates Ex-Vivo Cardiac Reperfusion Injury through Augmented Mitochondrial Oxidative Stress

“…Inter-strain differences were caused by changes to state-III respiration rates. In the IAA mitochondria, the calcium-induced stimulation of state-III respiration rate [52] was observed with pyruvate, but not with palmitoylcarnitine. This agrees perfectly with the increased glucose-oxidation rate observed in the hearts of these animals when RPP is augmented [53].…”