Lactate formation in muscle: In exercising skeletal muscle, NADH production (by glyceraldehyde 3-phosphate dehydrogenase and by the three NAD+-linked dehydrogenases of the TCA cycle, see p. 113) exceeds the oxidative capacity of the ETC. This results in an elevated NADH/NAD+ ratio, favoring reduction of pyruvate to lactate by LDH. Therefore, during intense exercise, lactate accumulates in muscle, causing a drop in the intracellular pH, potentially resulting in cramps. Much of this lactate eventually diffuses into the bloodstream and can be used by the liver to make glucose (see p. 118).
2.
Lactate utilization: The direction of the LDH reaction depends on the relative intracellular concentrations of pyruvate and lactate and on the ratio of NADH/NAD+. For example, in the liver and heart, this ratio is lower than in exercising muscle. Consequently, the liver and heart oxidize lactate (obtained from the blood) to pyruvate. In the liver, pyruvate is either converted to glucose by gluconeogenesis or converted to acetyl CoA that is oxidized in the TCA cycle. Heart muscle exclusively oxidizes lactate to carbon dioxide and water via the TCA cycle.
3.
Lactic acidosis: Elevated concentrations of lactate in the plasma, termed lactic acidosis (a type of metabolic acidosis), occur when there is a collapse of the circulatory system, such as with myocardial infarction, pulmonary embolism, and uncontrolled hemorrhage, or when an individual is in shock. The failure to bring adequate amounts of O2 to the tissues results in impaired oxidative phosphorylation and decreased ATP synthesis. To survive, the cells rely on anaerobic glycolysis for generating ATP, producing lactic acid as the end product. [Note: Production of even meager amounts of ATP may be lifesaving during the period required to reestablish adequate blood flow to the tissues.] The additional O2 required to recover from a period when O2 availability has been inadequate is termed the O2 debt. [Note: The O2 debt is often related to patient morbidity or mortality. In many clinical situations, measuring the blood levels of lactic acid allows the rapid, early detection of O2 debt in patients and the monitoring of their recovery.]
L. Energy yield from glycolysis
Despite the production of some ATP by substrate-level phosphorylation during glycolysis, the end product, pyruvate or lactate, still contains most of the energy originally contained in glucose. The TCA cycle is required to release that energy completely (see p. 109).
1. Anaerobic glycolysis: A net of two molecules of ATP are generated for each molecule of glucose converted to two molecules of lactate (Fig. 8.22). There is no net production or consumption of NADH.
2. Aerobic glycolysis: The generation of ATP is the same as in anaerobic glycolysis (that is, a net gain of two ATP per molecule of glucose). Two molecules of NADH are also produced per molecule of glucose. Ongoing aerobic glycolysis requires the oxidation of most of this NADH by the ETC, producing three ATP for each NADH molecule entering the chain (see p. 77). [Note: NADH cannot cross the inner mitochondrial membrane, and substrate shuttles are required (see p. 79).]
VI. HORMONAL REGULATION