Pyruvate Reduction to lactate

Lactate, formed from pyruvate by LDH, is the final product of anaerobic glycolysis in eukaryotic cells (Fig. 1). Reduction to lactate is the major fate for pyruvate in tissues that are poorly vascularized (for example, the lens and cornea of the eye and the kidney medulla) or in RBC that lack mitochondria.

Figure 1: Interconversion of pyruvate and lactate by lactate dehydrogenase (LDH). NAD(H) = nicotinamide adenine dinucleotide.
1. 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) 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 .
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.]

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