MDH1 encodes the mitochondrial isozyme of malate dehydrogenase (3) that converts malate to oxaloacetate in the tricarboxylic acid (TCA) cycle, a central hub of metabolism (1; see the TCA cycle pathway page for more details). Other malate dehydrogenase isozymes include Mdh2p, the cytosolic form involved in gluconeogenesis, and Mdh3p, the peroxisomal form involved in the glyoxylate cycle. In the aerobic utilization of glucose, pyruvate generated from glucose via glycolysis is oxidatively decarboxylated to form acetyl CoA, which is completely oxidized to carbon dioxide plus water in the TCA cycle. The TCA cycle also generates intermediates for biosynthesis of amino acids, fatty acids, heme, and for gluconeogenesis.

Mdh1p is also a component of a NADH shuttle that regulates the NAD/NADH ratio in the cytoplasm and mitochondria. The mitochondrion is impermeable to NAD and NADH, but in the malate-aspartate shuttle, Mdh1p and Aat1p convert malate to oxaloacetate and then to aspartate inside the mitochondrion, producing NADH from NAD; aspartate is transported to the cytoplasm and there converted to oxaloacetate and then to malate by Aat2p and Mdh2p, producing NAD from NADH (4). The fact that overexpressing Mdh1p extends replicative lifespan, in combination with additional genetic evidence, suggests that this shuttle pathway may play a major role in calorie restriction-mediated lifespan extension (5). Consistent with this, MDH1 expression is upregulated during calorie restriction (6).

Mdh1p is found in the mitochondrial matrix, and at least a portion exists in a large supramolecular complex in mitochondria that includes NADH dehydrogenases and other TCA cycle enzymes, which may facilitate channelling of metabolites between enzymes (3).

Last updated: 2008-09-09