Question

2. (2 pts) Explain the purpose for why lactate is produced in exercising muscle rather increasing the rate of shuttling of pyruvate into the mitochondria for oxidative phosphorylation?

Answer 1

Lactate, the conjugate base of lactic acid occurring in aqueous biological fluids, has been derided as a “dead-end” waste product of anaerobic metabolism. Catalyzed by the near-equilibrium enzyme lactate dehydrogenase (LDH), the reduction of pyruvate to lactate is thought to serve to regenerate the NAD+necessary for continued glycolytic flux. Reaction kinetics for LDH imply that lactate oxidation is rarely favored in the tissues of its own production.the continuous formation and oxidation of lactate serves as a mitochondrial electron shuttle, whereby lactate generated in the cytosol of the cell is oxidized at the mitochondria of the same cell.

  The reduction of pyruvate to lactate, catalyzed by lactate dehydrogenase (LDH; Pyruvate + NADH + H+ ⇌ Lactate + NAD+) in the cytosol of many cells, has been regarded as a metabolic “dead-end” because lactate can only rejoin the metabolic network via pyruvate. In mammals, the LDH reaction is also considered to be “near-equilibrium” ,meaning that the reaction is regulated chiefly by the concentrations of its reactants and products, rather than by more sophisticated means of allosteric regulation or covalent modification.Because the equilibrium for the LDH reaction lies far to the right (i.e., lactate formation favored) the implication might be that LDH rarely favors the reverse reaction .

The lactate is central to the shuttling of energetic substrate between the cytosol (glycolysis) and the mitochondria (oxidative phosphorylation).

Due to the impermeability of the inner mitochondrial membrane to NAD+ and NADH, NADH generated by glycolysis under aerobic conditions depends on the indirect transfer of reducing equivalents into the mitochondria via the malate-aspartate shuttle (MAS) and glycerol-phosphate shuttle. These shuttles are also thought to regenerate cytosolic NAD+ necessary to support glycolytic flux at the NAD+-requiring glyceraldehyde 3-phosphate dehydrogenase reaction. The MAS has been demonstrated to be the predominant means by which this occurs in most oxidative tissues, and appears to constitute the principal NADH shuttle in mature neurons.It is also well established that during conditions of increased cellular energy demand and/or increased glycolytic flux (e.g., during strenuous exercise), as well as hypoxia, that the concentration of lactate will increase as the LDH reaction facilitates increased rates of cytosolic NAD+ regeneration .