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substrates to support adequate cellular levels of high-energy phosphate compounds such as adenosine triphosphate (ATP). The general consequences of this have been studied in a variety of organs, especially in the brain, which is extraordinarily sensitive to damage from ischemia and reperfusion.
ATP can be generated by anaerobic metabolism, which produces a net 2 moles of ATP for each mole of glucose metabolized. The end product of this pathway is pymvate, which is then normally transferred to further oxidative metabolism in the mitochondria. Mitochondrial aerobic metabolism is much more efficient than anaerobic metabolism in the production of ATP; in the aerobic system 36 moles of ATP are generated for each mole of glucose oxidized ultimately to carbon dioxide (CO2) and water (H2O). When aerobic metabolism fails because of inadequate O2 delivery, persistent anaerobic metabolism and the conversion of accumulated pyruvate to lactate by pyruvate dehydrogenase lead to cellular accumulation of unoxidized reducing equivalents and decreased pH because of lactic acidosis.
The mitochondrial metabolism of the substrate generates electrons, which are added to O2 one electron at a time. That is, the reduction of O2 is stepwise, and the reaction can be written as follows:
where e- is an electron, *O2- is superoxide, H2O2 is hydrogen peroxide, *OH is the hydroxyl radical, and OH- is the hydroxide ion. Mitochondria utilize the energy derived from the reduction of O2 to drive the pumping of protons out of the inner mitochondrial volume into the space between the inner and outer mitochondrial membranes. The phosphorylation of adenosine diphosphate (ADP) to generate ATP is then driven from the energy stored in the hydrogen ion gradient across the inner mitochondrial membrane. Two aspects of this system that are very important to understanding the role of mitochondria in postischemic reperfusion injury are the single-electron reduction of O2 and the hydrogen ion gradient across the inner mitochondrial membrane.
Depletion of ATP occurs during ischemia; this develops most rapidly in the brain, where the concentration of ATP is reduced to near zero within approximately 5 minutes of complete ischemia (reviewed by O'Neil et al., 1996). This ATP depletion degrades the energy-dependent maintenance of ionic gradients across the plasmalemma, and sodium ions (Na+) and calcium ions (Ca2+) enter the cell, and potassium ions (K+) exits the cell down their respective concentration gradients. The Ca2+ concentration in the extracellular fluid and within the endoplasmic reticulum (ER) is about 104 greater than the cytosolic Ca2+ concentration, and early massive overload of the cytosol with Ca2+ is a major consequence of tissue ischemia.
Unlike Na+ and K+, Ca2+ is both a signaling molecule (Clapham, 1995) and a cofactor for a number of important enzymes. Important enzymatic consequences of ischemia-induced cytosolic Ca2+ overload and ER Ca2+ depletion are activation of (1) phospholipases, (2) the proteolytic enzyme µ-calpain, (3) the