Most of the energy derived from the oxidation of glucose is not extracted directly as ATP, but as reduced NADH that transfers high-energy electrons to the electron transport chain in the inner mitochondrial membrane. This NADH comes primarily from the Krebs cycle in the mitochondrial matrix and is therefore directly accessible to electron transport. NADH generated during glycolysis cannot reach the electron transport chain directly however and there is no direct mechanism for the transfer of NADH across the mitochondrial membrane. Instead shuttle mechanisms have evolved to move the energy of reduced NADH across the membrane in the form of other reduced molecules. One shuttle is the glycerophosphate shuttle and another is the malate-aspartate shuttle. The malate-aspartate shuttle occurs in mammalian tissues. First, oxaloacetate on the cytoplasmic side is reduced by NADH, creating malate and NAD+. Malate and the electrons it carries are transported into the mitochondria across the inner mitochondrial membrane, in exchange for alpha-ketoglutarate, which is transported out of the mitochondria. Once inside, the energy in malate is extracted again by reducing NAD+ to make NADH, regenerating oxaloacetate. This NADH is then free to transfer its high energy electrons to the electron transport chain. The oxaloacetate is transaminated with glutamate to make aspartate and alpha-ketoglutarate. Aspartate is returned to the cytosol by the aspartate-glutamate transporter, which moves glutamate into the mitochondria as it transports aspartate out. The overall result is that NADH is transported into the mitochondria, and can be used to generate 3 ATP per every NADH transported in from the cytosol, a very efficient process.
Contributor: Glenn Croston, PhD.
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