FIGURE 1.

Schematic representation of the mitochondrial electrophysiological and metabolic processes and their interactions, as described by the model. The model takes into account oxidative phosphorylation and matrix-based processes in mitochondria. The tricarboxylic (TCA) cycle of the mitochondrial matrix is fed by acetyl CoA (AcCoA), which is the point of convergence for the oxidation of fatty acids and glucose, the two main substrates of the heart. The TCA (or Krebs) cycle completes the oxidation of AcCoA to CO₂ and produces NADH and FADH₂, which provide the driving force for oxidative phosphorylation. NADH and FADH₂ are oxidized by the respiratory chain and the concomitant pumping of protons across the mitochondrial inner membrane establishes an electrochemical gradient, or proton motive force (Δμ_H), composed of an electrical gradient (ΔΨ_m) and a proton gradient (ΔpH). This proton motive force drives the phosphorylation of matrix ADP to ATP by the F₁F₀-ATPase (ATP synthase). The large ΔΨ_m of the inner membrane (−150 to −200 mV; matrix negative with respect to the cytoplasm) also governs the electrogenic transport of ions, including the cotransport of ATP and ADP by the adenine nucleotide translocator, Ca²⁺ influx via the Ca²⁺ uniporter and Ca²⁺ efflux via the Na⁺/Ca²⁺ antiporter (Magnus and Keizer, 1997). The model also accounts for the explicit dependence of the TCA cycle enzymes isocitrate dehydrogenase and α-ketoglutarate dehydrogenase on Ca²⁺. In this way, the rate of Ca²⁺ uptake by mitochondria is involved in membrane energization through the TCA cycle and oxidative phosphorylation, which are described in detail in the Appendix. Key to symbols: The concentric circles with an arrow across located at the inner mitochondrial membrane represent the ΔΨ_m. Dotted arrows indicate regulatory interactions either positive (arrowhead) or negative (−).