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"Diagram Illustrating the Malate-Asparate Shuttle Pathway"

The malate-aspartate shuttle (sometimes also the malate shuttle) is a biochemical system for translocating electrons produced during glycolysis across the impermeable inner membrane of the mitochondrion for oxidative phosphorylation in eukaryotes. This allows the reduction equivalents of the cofactor NADH produced in the cytosol to reach the electron transport chain in the mitochondria and generate ATP. The shuttle system is required because the inner membrane is impermeable to NADH and its oxidized form NAD⁺.

It consists of four protein parts:

• malate dehydrogenase in the mitochondrial matrix and intermembrane space.
• aspartate aminotransferase in the mitochondrial matrix and intermembrane space.
• Malate-alpha-Ketoglutarate antiporter in the inner membrane.
• Glutamate-Aspartate antiporter in the inner membrane.

The key enzyme in the malate-aspartate shuttle is malate dehydrogenase; in the cytosol, it reacts with oxaloacetate and NADH to produce malate and NAD⁺. The first of two antiporters in the inner membrane imports malate into the mitochondrial matrix and simultaneously exports alpha-ketoglutarate into the cytosol. In the matrix, the reverse reaction catalyzed by the same enzyme produces NADH and oxaloacetate from the newly imported malate and internal NAD⁺. A transaminase enzyme in the matrix reacts oxaloacetate and glutamate to form aspartate and alpha-ketoglutarate. A second antiporter exports aspartate from the matrix back to the cytoplasm while simultaneously importing glutamate. Finally, in the cytosol, another transaminase reacts aspartate and alpha-ketoglutarate to re-form glutamate and oxaloacetate.

The net effect of the malate-aspartate shuttle is purely redox: NADH in the cytosol is oxidized to NAD⁺, and NAD⁺ in the matrix is reduced to NADH. The NAD⁺ in the cytosol can then be reduced again by another round of glycolysis, and the NADH in the matrix can be used to pass electrons to the electron transport chain so that ATP can be synthesized.

Since the malate-aspartate shuttle regenerates NADH inside of the mitochondrial matrix it is capable of maximizing the number of ATP produced in glycolysis (2.5/NADH). Compare this to the glycerol 3-phosphate shuttle, which donates electrons to Complex II of the electron transport chain (similar to FADH2), and is only capable of generating 1.5 ATP per NADH generated in glycolysis.

• Lodish, H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J. (2004). Molecular Cell Biology, 5th, New York: WH Freeman.

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