When nutrients become locally limited, several cancers, including pancreatic, glioblastoma, and ovarian, hijack stromal glutamine synthesis as an alternative supply line to fulfill their increased demands. In cells with high proliferative rates (e.g., cancer cells, activated T lymphocytes), glutamine demand outweighs supply and environmental access becomes “conditionally essential”. Activity of GS is well described in the brain as a means of removing excess ammonia by astrocytes, and dysfunctional ammonia metabolism can lead to hepatic encephalopathy and cerebral edema. Glutamine supply is derived from both dietary sources and de novo synthesis, the latter of which requires glutamate and ammonia and is catalyzed by glutamine synthetase (GS) in the cytosol. Under physiological conditions, glutamine is one of the most abundant amino acids in circulation. Further, we discuss key metabolic inputs and outputs of amino acid metabolism that involve mammalian mitochondria with a specific focus on how activity of these pathways is regulated and dysregulated in human disease. Here we review how plasma membrane and mitochondrial transporters act as important interfaces between compartmentalized metabolic pathways. Notably, amino acids do not freely diffuse across the inner mitochondrial membrane and require specific transport proteins to facilitate their exchange. Mitochondria, in addition to canonical ATP generation, play an important biosynthetic role and amino acid metabolism is intricately linked to this functional output. Many changes to proto-mitochondrial functions have evolved since the initial endosymbiosis occurred, complicating our understanding of the metabolic reasoning behind the symbiotic relationship however, present day mitochondria are complex organelles that participate in broad and critical cellular and biochemical roles. The mitochondrion is one such organelle, originating as symbiotic α-proteobacteria that co-evolved within a proto-eukaryote host. Metabolic compartmentalization allows for specific pools of enzymes, substrates, and cofactors to be maintained within each organelle, providing unique subcellular conditions to fulfill specialized biochemical functions.
The compartmentalization of metabolic pathways into one or more subcellular organelles is, except for rare cases, a fundamental characteristic of eukaryotic organisms.
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