Revisiting concepts of mitochondrial transport and energy metabolism in health and cancer

Although our understanding of mitochondrial processes has expanded substantially, the contributions of metabolite transport and energy metabolism to mitochondrial function in health and disease remain incompletely characterized. The transport and metabolism of key metabolites, including oxaloacetate, L-lactate and D-lactate, are mediated by distinct transporters and mitochondrial enzymes that together influence cellular bioenergetics in normal and neoplastic tissues. This review reassesses mechanistic aspects of mitochondrial shuttles, gluconeogenesis and the Cori cycle, the mitochondrial transport and oxidation of L-lactate, the Warburg effect, and the methylglyoxal pathway. Emphasis is placed on evidence supporting mitochondrial uptake and metabolism of oxaloacetate and lactate isomers and on the implications of these processes for redox balance, anaplerosis, and biosynthesis in cancer. I propose that a fuller integration of metabolite transport phenomena into models of cellular metabolism is necessary to refine current concepts of mitochondrial physiology and pathophysiology.