Failure to supply energy to match the body's demands limits the functional reserve capacity, and under certain periods of stress, such as ischemia, can lead to irreversible cell and tissue damage. This matching is critical in tissues with high and rapidly fluctuating metabolic rates such as the heart. Mitochondria are the main ATP suppliers to meet cellular demands. The fuel used by mitochondria is transported across the inner mitochondrial membrane to the matrix and produces a source of electrons whose redox-potential energy is, in turn, harnessed by the electron transport chain. The flux of electrons is reflected in oxygen consumption. The energy released from this electron flow is used to transport protons out of the matrix across the inner mitochondrial membrane forming a gradient whose proton-motive force drives ATP synthase to make ATP. This """"""""upstream"""""""" regulation is known as the """"""""push"""""""" mechanism. A complete description of the ATP synthase control mechanisms is still lacking. Two general mechanisms have been suggested to serve as key regulators: 1) ADP and Pi concentrations;ATP utilization/hydrolysis in the cytosol increases ADP and Pi fluxes to mitochondria and hence the amount of available substrates for ATP production increases;2) Ca2+ concentration;ATP utilization/hydrolysis is coupled to changes in free cytosolic calcium and mitochondrial Ca2+, the latter controlling Ca2+-dependent activation of certain mitochondrial reaction-rate-determining enzymes taking part in ATP production. At high levels of energy demand the question arises whether parallel to the """"""""push"""""""" mechanism signals acting on ATP synthase could also facilitate the electron transport chain redox flux, enhancing the efficiency of ATP production. This effect simulates an apparent additional """"""""pull"""""""" on the upstream flux, which causes as a specific proportionate increase in respiration. Proof of such a """"""""pull"""""""" mechanism regulated by Ca2+ and its target has not been demonstrated to-date. Cardiomyocytes contract in response to driven cyclic 'increases'in cytosolic Ca2+ in a response to electrically stimulation. As a consequence of the levels of contractile work, ATP is proportionately utilized by the contractile elements. Therefore, from the demand point of view Ca2+ is a direct effector that might be well positioned to play a role in the energy matching regulatory mechanisms. A correlation has also been shown between cytosolic and mitochondrial Ca2+. Ca2+ enters the mitochondria through the mitochondrial uniporter and is extruded by the mitochondrial Na+/Ca2+ exchanger. This results in mitochondrial Ca2+ accumulation in response to an increase in stimulation frequency or Ca2+ transient amplitude. Therefore, Ca2+ levels in the mitochondria reflect changes in both myocardial work and ATP consumption and, hence, the demand for ATP. It was shown that mitochondrial Ca2+ can activate the mitochondrial enzymes taking part in ATP production. Therefore, changes in mitochondrial Ca2+ during electrical stimulation are linked to changes in ATP supply and demand. We and others have shown that small changes in mitochondrial volume can regulate respiration and in turn energy production. It is also known that the Ca2+ environment may regulate mitochondrial volume in isolated mitochondrial suspension raising the question whether physiological changes in Ca2+ via increasing electrically stimulated Ca2+ cycling would act in this way. We found that while increasing electrically stimulated, physiological Ca2+ cycling does not detectibly change the 'diastolic'mitochondrial long- and short-axis dimensions (i.e, volume) shortly (2.5 min) after the transition from rest to low or higher workloads, it nevertheless caused an increase in cell respiration (and in turn facilitated energy production) in both conditions. These results were in contrast to that observed by others in the isolated mitochondria models. Additionally, we found that the mechanisms that control ATP supply from the hearts mitochondria consist of both 'push'and 'pull'mechanisms and that 'pull'mechanism directly targets ATP synthase. We identified that the 'pull'mechanism is controlled by mitochondrial Ca2+ and can be further facilitated by pharmacologically regulating mitochondrial volume. At low cardiac workload, the 'push'mechanism is sufficient to match ATP supply and demand, and the mitochondrial transmembrane ADP/Pi gradient is presumably sufficient to drive the 'push'and 'pull'mechanisms. However, under the same experimental conditions, pharmacological induction of a regulatory mitochondrial volume increase was found to facilitate mitochondrial Ca2+ entry responsible for further pushing respiration, whereas at higher workloads, mitochondrial Ca2+ entry did not require such facilitation, and in turn was sufficient and essential to drive both """"""""push"""""""" and 'pull'effects on respiration. Moreover, pharmacologically-enhanced mitochondrial Ca2+ accumulation (without changing cytosolic Ca2+) was also found to push respiration. Facilitation of these 'push'and 'pull'mechanisms is being examined as a potential treatment to reverse signaling defects in matching ATP supply and demand, such as occurs in heart failure which afflicts millions of people, especially the elderly population.
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