Mitochondrial metabolism of glutamine and glutamate and its physiological significance

Abstract

Although several reviews on the metabolism of glutamine and glutamate have been published, this subject has not previously been reviewed with particular reference to the importance of the mitochondria. Throughout this review we have emphasized the key role of intramitochondrial reactions in the control of glutamine and glutamate metabolism in various tissues. We have also tried to integrate the large amount of related work performed on isolated mitochondria. The properties of the purified enzymes involved in these metabolic pathways are now well characterized for many tissues, and researchers are beginning to recognize the significance of factors such as membrane permeability in determining the effective activity of enzymes in isolated mitochondria. Investigation of the regulation of glutamine and glutamate metabolism in isolated mitochondria is a prerequisite for understanding their metabolism and their physiological roles in intact tissue. Many problems in this area are still unresolved: the mechanism by which acidosis stimulates ammoniagenesis at the mitochondrial level in the kidney, the physiological role of glutamine in the liver, and the regulation of glutamine hydrolysis at the mitochondrial level in the small intestine. The compartmentation of glutamine and glutamate metabolism in brain and the reason for active oxidative metabolism of glutamine in tumor cells also require further investigation. Finally, the question of hormonal control of glutamine and glutamate metabolism in various tissues is still largely unexplored. The stimulation of liver glutaminase by glucagon, discussed in section v, is an example of a case in which a hormone acting at the cell membrane may influence the effective activity of an intramitochondrial enzyme. The mechanism of control of intramitochondrial enzymes by extracellular factors is one of the most important and interesting questions outstanding in the study of mitochondrial metabolism.