Malate-aspartate shuttle (MDH1/MDH2/GOT1/GOT2 + SLC25A11/SLC25A12)

The malate-aspartate shuttle is the principal mechanism by which reducing equivalents (cytosolic NADH generated in glycolysis) are transferred into the mitochondrial matrix for oxidation by the respiratory chain, in tissues such as heart, liver and brain. Because NADH itself cannot cross the inner mitochondrial membrane, the shuttle moves the electrons as malate: in the cytosol, malate dehydrogenase 1 (MDH1) reduces oxaloacetate to malate, consuming a cytosolic NADH; the malate is imported by the oxoglutarate/malate carrier (SLC25A11, OGC) in exchange for 2-oxoglutarate; in the matrix, malate dehydrogenase 2 (MDH2) re-oxidises malate to oxaloacetate, regenerating matrix NADH that feeds Complex I. Oxaloacetate cannot cross the membrane either, so it is transaminated with glutamate to aspartate by mitochondrial aspartate aminotransferase (GOT2, PLP-dependent); the aspartate is exported by the Ca2+-regulated aspartate-glutamate carrier (SLC25A12, AGC1/aralar) in exchange for cytosolic glutamate, and cytosolic aspartate aminotransferase (GOT1) regenerates oxaloacetate and 2-oxoglutarate to close the cycle. The AGC1 antiport, being electrogenic and effectively unidirectional, gives the shuttle its net direction. Defects in these components cause disease: SLC25A12/AGC1 deficiency causes a hypomyelinating encephalopathy (global cerebral hypomyelination / epilepsy), MDH2 and GOT2 deficiencies cause early infantile epileptic encephalopathy, and the shuttle is a key node in cancer redox metabolism.