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. 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 and its target has not been demonstrated to-date.? ? We found that the mechanisms that control ATP supply from the heart's mitochondria consist of both """"""""push"""""""" and """"""""pull"""""""" mechanisms and that the """"""""pull"""""""" mechanism directly targets ATP synthase. We identified that the """"""""push"""""""" and """"""""pull"""""""" mechanisms are controlled by mitochondrial volume and Ca2+. At low cardiac workloads, a regulatory mitochondrial volume increase was found to facilitate mitochondrial Ca2+ entry responsible for pushing respiration (and in turn facilitating energy production), whereas at higher workloads, mitochondrial Ca2+ entry did not require such facilitation, and in turn was sufficient to drive both a push and pull effects on respiration. Identification of the matching mechanisms between ATP demand and supply could allow development of agents with better specificity that could potentially lead to the discovery of effective treatments, for example, for pathologies involving a failure of energy supply/demand matching, such as occurs in heart failure which afflicts millions of persons worldwide.
