The concept is particularly supported by recent research in neuronal cells ( Gellerich et al., 2012, 2013 Rueda et al., 2014). Components of such a concept have been demonstrated in heart ( Safer et al., 1971) and skeletal muscle ( Schantz, 1986), were later expanded to a lactate shuttle perspective ( Stainsby and Brooks, 1990 Brooks et al., 1999) and comprehensively reviewed ( Gladden, 2004) and again commented upon ( Gladden, 2007). The purpose of the current Perspective is to forward a model in which lactate is central to the shuttling of energetic substrate between the cytosol (glycolysis) and the mitochondria (oxidative phosphorylation). However, experimental evidence increasingly belies any notion that LDH operates unidirectionally in vivo, and supports that lactate serves as an important metabolic fuel for many tissues, including skeletal ( Brooks et al., 1991 Bergman et al., 1999 Donovan and Pagliassotti, 2000) and cardiac muscle ( Gertz et al., 1988 Chatham et al., 2001), liver ( Skilleter and Kun, 1972 Kline et al., 1986), and brain ( Schurr et al., 1988 Bouzier-Sore et al., 2006 Wyss et al., 2011 Funfschilling et al., 2012 reviewed in Barros, 2013). Indeed, the mass action ratio (/) necessary for appreciable lactate oxidation would need to exceed the equilibrium constant for LDH. Because the equilibrium for the LDH reaction lies far to the right (i.e., lactate formation favored) ( Williamson et al., 1967), regardless of LDH isoform ( Quistorff and Grunnet, 2011a, b), the implication might be that LDH rarely favors the reverse reaction (i.e., lactate oxidation) in vivo. In mammals, the LDH reaction is also considered to be “near-equilibrium” ( Spriet et al., 2000 Quistorff and Grunnet, 2011a, b), 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 ( Crabtree and Newsholme, 1978). 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” ( Luft, 2001 Quistorff and Grunnet, 2011a), or perhaps more aptly, a metabolic cul de sac ( Barros, 2013), because lactate can only rejoin the metabolic network via pyruvate. Introduction: Lactate Dehydrogenase Reaction Among the requisite features of such a model, significant compartmentalization of LDH, much like the creatine kinase of the phosphocreatine shuttle, would facilitate net cellular lactate oxidation in a variety of cell types. From this perspective, an intracellular lactate shuttle operates much like the malate-aspartate shuttle (MAS) it is also proposed that the two shuttles are necessarily interconnected in a lactate-MAS. In the current Perspective, a model is forwarded in which 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.

However, a substantial body of research directly contradicts any notion that LDH invariably operates unidirectionally in vivo.

Reaction kinetics for LDH imply that lactate oxidation is rarely favored in the tissues of its own production. 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. Lactate, the conjugate base of lactic acid occurring in aqueous biological fluids, has been derided as a “dead-end” waste product of anaerobic metabolism. Francis Xavier University, Antigonish, NS, Canada

Malate oxaloacetate shuttle