Contribution of ATP synthase to stimulation of respiration by Ca2+ in heart mitochondria

Abstract

A variety of experimental conditions were applied with the aim to estimate the correlation between the contribution of ATP synthase to the respiratory flux control and the calcium-induced activation of succinate oxidation in heart mitochondria isolated from rat, rabbit and guinea pig. The sensitivity of respiration in heart mitochondria to the decrease in temperature from 37 degrees C to 28 degrees C decreases in the order rabbit > guinea pig > rat. Ca2+ effect on succinate oxidation rate in state 3 respiration was species- and temperature-dependent and ranged from 0 (rat, 37 degrees C) to +44% (rabbit, 28 degrees C). For mitochondria from all experimental animals, the increase of Ca2+ in physiological range of concentration did not change state 2 respiration rate, and the stimulatory effect of Ca2+ on state 3 respiration was more pronounced at 28 degrees C than at 37 degrees C. The respiratory subsystem was sensitive to Ca2+ ions only in rabbit heart mitochondria. A high positive correlation between Ca2+ ability to stimulate succinate oxidation in state 3 and the control exerted by ATP synthase over the respiratory flux provides argument confirming stimulation of ATP synthase by Ca2+ ions.

Stimulatory Effects of Calcium on Respiration and NAD(P)H Synthesis in Intact Rat Heart Mitochondria Utilizing Physiological Substrates Cannot Explain Respiratory Control in Vivo

“…7B has a slope that is lower compared with the data in Fig. 3 (A and B) (5) showed that the cardiac mitochondrial respiratory response in the rat has a low calcium sensitivity with succinate as a substrate compared with rabbit and guinea pig. Similarly, the low Ca 2ϩ sensitivity of mitochondrial respiration and NAD(P)H fraction with pyruvate/malate observed in our study could potentially be species-specific.…”

“…The results plotted in Fig. 7 (A (respiration) and B (redox versus respiration)) show that respiration was stimulated from 0 to 100 nM Ca The effect of Ca 2ϩ on the respiration and redox responses of cardiac mitochondria has been found to be dependent on the substrates used, the species of the animal, and the experiment temperature (5,6,19,21). The cited studies reported that the stimulatory effect of Ca 2ϩ on State 3 mitochondrial respiration with pyruvate/malate was between 20 and 30%; therefore, subsaturating 2-oxoglutarate or saturating glutamate and malate were used as substrates to demonstrate Ca 2ϩ stimulation of mitochondrial State 3 respiration.…”

“…More properly, such a mechanism would be an example of open-loop control, where parallel Ca 2ϩ -dependent pathways would stimulate ATP utilization and synthesis. Cytosolic free Ca 2ϩ , which is a signal coupling cardiac electrical excitation to mechanical contraction, thereby increasing ATP demand, was identified as a putative open-loop controller activating mitochondrial matrix dehydrogenases and F 1 F 0 -ATPase in studies on isolated mitochondria utilizing glutamate/malate (4) or 2-oxoglutarate alone (5,6) as substrate, whereas pyruvate is a physiological substrate entering the terminal oxidative pathway in the mitochondrial TCA cycle. In this study, we measured the respiration and redox responses of mitochondria to extramitochondrial free Ca 2ϩ when utilizing the physiological substrates pyruvate and malate at saturating, physiological, and subphysiological concentrations at physiological temperature and free magnesium (Mg 2ϩ ) concentration.…”

Age-related changes of myocardial ATP supply and demand mechanisms

“…Ca 2+ can affect ATP supply by stimulating PDH activity and other dehydrogenase mechanisms, such as isocitrate and α-ketoglutarate (reviewed in [69]). Whether Ca 2+ directly activates ANT remains controversial [70]. It has also been reported that an increase in mitochondrial Ca 2+ level can regulate mitochondrial matrix volume [71] which in turn can elevate respiration in isolated mitochondria suspensions.…”

Carnitine regulates myocardial metabolism by Peroxisome Proliferator-Activated Receptor-alpha (PPARalpha) in alcoholic cardiomyopathy

“…However, synthesis of ATPase cannot compensate for extra energy consumption following chronic alcohol intake. Down-regulated expression of ATPase mRNA and protein, corresponding to transcription and post-transcriptional regulation, elicits alteration of enzymatic structure and loss of enzyme content [30–32]. These changes in structure and content of enzyme may lead to cellular energy deficiency.…”