A Lactatic Perspective on Metabolism

The cell-to-cell lactate shuttle was introduced in 1984 and has been repeatedly supported by studies using a variety of experimental approaches. Because of its large mass and metabolic capacity, skeletal muscle is probably the major component of the lactate shuttle in terms of both production and consumption. Muscles exercising in a steady state are avid consumers of lactate, using most of the lactate as an oxidative fuel. Cardiac muscle is highly oxidative and readily uses lactate as a fuel. Lactate is a major gluconeogenic substrate for the liver; the use of lactate to form glucose increases when blood lactate concentration is elevated. Illustrative of the widespread shuttling of lactate, even the brain takes up lactate when the blood level is increased. Recently, an intracellular lactate shuttle has also been proposed. Although disagreements abound, current evidence suggests that lactate is the primary end-product of glycolysis at cellular sites remote from mitochondria. This lactate could subsequently diffuse to areas adjacent to mitochondria. Evidence is against lactate oxidation within the mitochondrial matrix, but a viable hypothesis is that lactate could be converted to pyruvate by a lactate oxidation complex with lactate dehydrogenase located on the outer surface of the inner mitochondrial membrane. In another controversial area, the role of lactic acid in acid-base balance has been hotly debated in recent times. Careful analysis reveals that lactate, not lactic acid, is the substrate/product of metabolic reactions. One view is that lactate formation alleviates acidosis, whereas another is that lactate is a causative factor in acidosis. Surprisingly, there is little direct mechanistic evidence regarding cause and effect in acid-base balance. However, there is insufficient evidence to discard the term "lactic acidosis."