Matching ATP supply and demand in mammalian heart: in vivo, in vitro, and in silico perspectives

Abstract

Although the heart rapidly adapts cardiac output to match the body's circulatory demands, the regulatory mechanisms ensuring that sufficient ATP is available to perform the required cardiac work are not completely understood. Two 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; and (2) Ca2+ concentration--ATP utilization/hydrolysis is coupled to changes in free cytosolic calcium and mitochondrial calcium, the latter controlling Ca2+-dependent activation of mitochondrial enzymes taking part in ATP production. Here we discuss the evolving perspectives of each of the putative regulatory mechanisms and the precise molecular targets (dehydrogenase enzymes, ATP synthase) based on existing experimental and theoretical evidence. The data synthesis can generate novel hypotheses and experimental designs to solve the ongoing enigma of energy supply-demand matching in the heart.

Figure 1

Bioenergetics scheme of mitochondrial membranes and matrix. The oxidative phosphorylation complexes are located in the inner mitochondrial membrane. The Krebs cycle produces a source of electrons whose redox-potential energy is, in turn, harnessed by the electron transport chain. The complement of ion channels that maintain the ionic gradients that establish the membrane potential ΔΨ_m, includine the Ca²⁺ uniporter, Na⁺/Ca²⁺ exchanger, Na⁺/K⁺ exchanger, adenine nucleotide translocator and proton leak.

Figure 2

Proposed “push” and “pull” regulatory mechanisms. The solid lines represent connections that are well established. The dotted lines represent proposed “push” mechanisms, and the dashed lines represent the “pull” mechanisms. Appropriate citations are indicated adjacent to the connecting arrows.