Glutamine-Derived Aspartate Biosynthesis in Cancer Cells: Role of Mitochondrial Transporters and New Therapeutic Perspectives

SIMPLE SUMMARY: In recent years, aspartate has been increasingly acknowledged as a critical player in the metabolism of cancer cells which use this metabolite for nucleotide and protein synthesis and for redox homeostasis. Most intracellular aspartate derives from the mitochondrial catabolism of glutamine. To date at least four mitochondrial transporters have been involved in this metabolic pathway. Their involvement appears to be cancer type-specific and dependent on glutamine availability. Targeting these mitochondrial transporters may represent a new attractive strategy to fight cancer. The aim of this review is to dissect the role of each of these transporters in relation to the type of cancer and the availability of nutrients in the tumoral microenvironment. ABSTRACT: Aspartate has a central role in cancer cell metabolism. Aspartate cytosolic availability is crucial for protein and nucleotide biosynthesis as well as for redox homeostasis. Since tumor cells display poor aspartate uptake from the external environment, most of the cellular pool of aspartate derives from mitochondrial catabolism of glutamine. At least four transporters are involved in this metabolic pathway: the glutamine (SLC1A5_var), the aspartate/glutamate (AGC), the aspartate/phosphate (uncoupling protein 2, UCP2), and the glutamate (GC) carriers, the last three belonging to the mitochondrial carrier family (MCF). The loss of one of these transporters causes a paucity of cytosolic aspartate and an arrest of cell proliferation in many different cancer types. The aim of this review is to clarify why different cancers have varying dependencies on metabolite transporters to support cytosolic glutamine-derived aspartate availability. Dissecting the precise metabolic routes that glutamine undergoes in specific tumor types is of upmost importance as it promises to unveil the best metabolic target for therapeutic intervention.