The Krebs cycle, also known as the TCA cycle or Citric Acid cycle, is a biochemical pathway that facilitates the breakdown of glucose in a cell. Both citrate and malate involved in the citrate-malate shuttle are necessary intermediates of the Krebs cycle. Usually, oxaloacetate in the Krebs cycle is generated from the carboxylation of pyruvate in the mitochondrion; however, malate generated in the cytosol can also enter the mitochondrion through the transport protein located in the inner mitochondrial membrane to directly join the Krebs cycle.
The mitochondrial transport proteins are encoded by the SLC25 gene in humans and facilitate the transportation of various metabolites, including citrate and malate, in the Krebs cycle. These transport proteins control the flow of metabolites in and out of the inner mitochondrial membrane, which is impermeable to most molecules. They connect the carbohydrate metabolism of the Krebs cycle to fatty acid synthesis in lipogenesis by catalyzing the transportation of acetyl-CoA out of the mitochondrial matrix into the cytosol, which is done in the form of citrate export from the mitochondria to the cytosol. Cytosolic citrate, meaning citrate in the cytosol, is a key substrate for the generation of energy. It releases acetyl-CoA and provides NADPH for fatty acid synthesis, and, in subsequent pathways, generates NAD for glycolysis. Citrate also activates acetyl-CoA carboxylase, an enzyme that is essential in the fatty acid synthesis pathway.
Citrate-malate shuttle might partly or completely replace the function of the Krebs cycle in cancer cell metabolism.