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1. Introduction
Contrary to what previously thought, lactate is a glycolysis byproduct that can be produced and utilized continuously by various body cells, at rest, and even under conditions of adequately oxygenation [1–3]. It is a highly dynamic metabolite, and its shuttling through the interstitium and the bloodstream works as an important carbon source for oxidation in many tissues [4–7] or for liver gluconeogenesis [8, 9], especially in situations where an intense physical effort is required [10, 11]. In addition, it has been shown that lactate exposure decreases the activities of both the hexokinase and phosphofructokinase enzymes (PFK) and hence the muscle glycolysis in a dose-dependent manner [12, 13].
In the last few years, some studies have been published around lactate metabolism, mainly concerning its route of removal inside the cell, and a new hypothesis arose. Rather than the traditional view of Stainsby and Brooks [1], where lactate-to-pyruvate conversion occurs on the adjacencies of mitochondria, the intracellular lactate shuttle hypothesis (ILS) currently suggests that this chemical reaction takes place within mitochondria, more precisely in the intermembrane space [14, 15].
This new model requires the involvement of some proteins already known in the lactate dynamics, particularly the lactate dehydrogenase enzyme (LDH)—the protein responsible for the lactate oxidation and reduction—and the MCT1, one of the monocarboxylate transporter isoforms that are in charge for lactate transposing between tissues. The likely location of these two structures into mitochondria would allow that the lactate oxidation reaction and the subsequent transport of the newly formed pyruvate-to-the mitochondrial matrix could occur. Many studies support this hypothesis [16–21]. However, there is considerable disagreement about the presence of both proteins and hence lactate oxidation in the mitochondrial reticulum, mostly in skeletal muscle tissue.
Therefore, the aims of this review are to (1) expose the whole ongoing debate about the presence/absence of the ILS in key tissues that are exercise-related, (2) make a critical appraisal on lactate oxidation complex (LOX), probable mechanism by which lactate is used as an energy source by cells, and (3) comment on the recent discovery of lactate as a signaling molecule and also its presumed role in mitochondrial biogenesis. The knowledge about these issues is needed in understanding the energy supplies systems functioning and how they interact with each other...