Cardiac ischemia and the resultant lack of oxygen lead to cessation of aerobic metabolism, transition to anaerobic metabolism, accumulation of glycolytic byproducts such as succinate and lactate, a decrease in intracellular pH, and increases in cytosolic Na⁺ and Ca²⁺ (9). Without oxygen to accept electrons from complex IV, the ETC is inhibited, and NADH and FADH₂ accumulate. ATP production via complex V (also known as ATP synthase) stops, and the heart must rely on glycolysis as the predominant pathway for ATP generation. During ischemia, approximately 50% of the glycolytically generated ATP is consumed by the reverse mode of the F₁F₀-ATP synthase and used to maintain mitochondrial membrane potential (Δψ) (10, 199, 200). In the cytosol, glucose is metabolized to pyruvate and subsequently lactate, resulting in acidosis of the cytosol due to retention of protons from degradation of glycolytically generated ATP (9, 198). The increase in cytosolic proton concentration stimulates H⁺ efflux via the Na⁺/H⁺ exchanger (NHE) (120). Na⁺ that enters is not extruded due to dysfunction of the Na⁺/K⁺ pump. The increase in cytosolic Na⁺ stimulates plasma membrane Na⁺/Ca²⁺ exchanger (NCX), leading to an increase in cytosolic Ca²⁺ (120, 134, 201). An increase in mitochondrial Ca²⁺ has also been recently shown to occur during ischemia and is thought to lead to cell death through opening of the mitochondrial permeability transition pore (mPTP) (128, 129, 134). Opening of the pore has been shown to be regulated by cyclophilin D (CypD).