Abstract
Simple SummaryIn 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.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.
Highlights
For many years, following Otto Warburg’s pioneering work [1], biologists have focused their attention on glucose metabolism in cancer cells
The mitochondrial glutamine-derived aspartate once transported into the cytosol is converted through a series of enzymatic reactions to pyruvate and NADPH that cells use for reactive oxygen species (ROS) control [11,17]
The oxidative stress generated by this pathway was suggested to be the main cause of tumor initiation [123]. These results suggest that UCP2 has an opposite function in tumor initiation and maintenance/progression, the biochemical function of
Summary
For many years, following Otto Warburg’s pioneering work [1], biologists have focused their attention on glucose metabolism in cancer cells. Cancer cells convert most of the To glycolytic pyruvate lactate, even in the presence of oxygen [1,4,5], their survival and proliferation rely on mitochondrial activity glutamine enters several metabolic pathways in both the cytosol and the mitochondria. ASP, aspartate; GLN, glutamine; GLU, glutamate; Pi, phosphate; OA, oxaloacetate; MAL, malate; α-KG, α-ketoglutarate; KC, Krebs cycle; IMS, intermembrane space; GOT2, mitochondrial isoform of the glutamate-oxaloacetate transaminase The latter hypothesis poses another question: does glutamate enter into mitochondria through GC (Figure 1B) or AGC (Figure 1C)? Data reported in the literature support all of these scenarios in different contexts suggesting the route of transport depends on the cancer type and glutamine availability in the tumor microenvironment
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