Principles of Biochemistry, Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Electron Transport, Oxidative Phosphorylation, and Regulation of ATP Synthesis
Shuttle systems are involved in the oxidation of extramitochondrial NADH

The inner mitochondrial membrane NADH dehydrogenase can donate electrons only to NADH located within the matrix. Because the inner mitochondrial membrane is impermeable to external NADH found in the Cytosol, how can the NADH generated during Glycolysis—which takes place outside the Cell/35.html">Mitochondria—be reoxidized back to NAD⁺ by molecular oxygen via the Respiratory Chain?

As it turns out, specialized shuttle systems transport reducing equivalents from cytosolic NADH into the mitochondria indirectly. The most active of these is the malate-aspartate shuttle, which operates in the mitochondria of the Liver, Kidneys, and Heart. Figure 17-26 illustrates the operating principle of this system. First, cytosolic malate dehydrogenase transfers reducing equivalents from cytosolic NADH to cytosolic oxaloacetate, yielding malate. Carrying the reducing equivalents derived from cytosolic NADH, malate crosses the inner mitochondrial membrane into the matrix via a dicarboxylate transport system. Once inside the mitochondrion, malate transfers these reducing equivalents to matrix NAD⁺ in a reaction catalyzed by matrix malate dehydrogenase. This reduces NAD⁺ to NADH, which can now pass its electrons directly into the respiratory chain of the inner mitochondrial membrane. For every pair of electrons transferred to oxygen, three ATP molecules are synthesized. Other components of this shuttle system (Fig. 17-26) regenerate cytosolic oxaloacetate, which is necessary to prime the shuttle cycle for another round.

In Skeletal Muscle and Brain tissue, The transfer of reducing equivalents from NADH is mediated by a different type of shuttle system known as the glycerol phosphate shuttle. It differs from the aforementioned malate-aspartate shuttle in its final step. Specifically, it delivers reducing equivalents to the respiratory chain not at site 1, but at site 2. Consequently, The oxidation of NADH yields only two ATP molecules instead of three.

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Fig. 17-26. The malate-aspartate shuttle system for transferring reducing equivalents from cytosolic NADH into the mitochondrial matrix. Malate, carrying the reducing equivalents, is transported across the inner membrane via a dicarboxylate carrier system (A). These reducing equivalents are then transferred to matrix NAD⁺ by matrix malate dehydrogenase. The resulting NADH, now inside the matrix, is oxidized by the Mitochondrial Electron Transport chain coupled with Oxidative Phosphorylation. The product of the malate dehydrogenase reaction, oxaloacetate, cannot cross the membrane to return to the cytosol. Instead, it is converted by a transaminase into aspartate, which can be transported across the membrane by an amino acid carrier system (C). The purpose of the other reactions and transport system B is to regenerate cytosolic oxaloacetate. Transport system B mediates the exchange of glutamate for aspartate. System A exports a-ketoglutarate in exchange for incoming malate. Transaminases (Chap. 19) catalyze the reversible transfer of amino groups from glutamate to oxaloacetate:

Glutamate + Oxaloacetate ⇄ a-Ketoglutarate + Aspartate.