Figure 1.

Schematic representation of the interaction among mitochondrial electron shuttles and mitochondrial lactate (La⁻) oxidation (Kane, 2014; Ferguson et al., 2018). Mono- and dicarboxylate anions can move between the cytosol and the mitochondrial intermembrane space by crossing the outer mitochondrial membrane via the voltage-dependent anion channels (VDAC). Due to the action of the glycerol phosphate and malate-aspartate shuttles, the cytosolic NAD⁺/NADH ratio can be orders of magnitude greater than the mitochondrial matrix, but decreases during exercise along with decreasing mitochondrial membrane potential (ΔΨ) spanning the inner membrane (inset; (Sahlin et al., 1987)). The electrogenic transport of glutamate (Glu²⁻) across the inner mitochondrial membrane via the aspartate-glutamate exchanger (AGE) is a key regulator of mitochondrial lactate oxidation vis-à-vis aerobic glycolysis and the malate-aspartate shuttle. The putative mitochondrial lactate oxidation complex comprised of mLDH, CD147, cytochrome c oxidase, and monocarboxylate transporter is depicted (Hashimoto et al., 2006), as is a matrix mLDH (Brooks et al., 1999). In the text, we argue against the likelihood of LDH in the mitochondrial matrix and suggest that the necessity and/or role of the lactate oxidation complex requires further study. Abbreviations: 2-OG²⁻ 2-oxoglutarate, I Complex I/NADH oxidoreductase of the mitochondrial electron system, II Complex II/succinate dehydrogenase of the mitochondrial electron system, III Complex III of the mitochondrial electron transport system, IV/COX complex IV/cytochrome c oxidase, AAT aspartate aminotransferase, AGE Aspartate-glutamate exchanger, Asp²⁻ aspartate, C cytochrome c, cG3P DH cytosolic glycerol 3-phosphate dehydrogenase, CoA coenzyme A, DHAP²⁻ dihydroxyacetone phosphate, G3P²⁻ glycerol 3-phosphate, Glu²⁻ glutamate, LDH L-lactate dehydrogenase, Mal²⁻ malate, MCT monocarboxylate transporter, MDH malate dehydrogenase, mG3P DH mitochondrial glycerol 3-phosphate dehydrogenase, mLDH mitochondrial lactate dehydrogenase, MOE malate-2-oxoglutarate exchanger, MPC mitochondrial pyruvate carrier, OAA²⁻ oxaloacetate, PDH pyruvate dehydrogenase complex, Pyr− pyruvate, Q quinone, TCA cycle tricarboxylic acid cycle