ATP Synthesis:- Shuttle Systems Indirectly Convey Cytosolic NADH into Mitochondria for Oxidation
The NADH dehydrogenase of the inner mitochondrial membrane of animal cells can accept electrons only from NADH in the matrix. Given that the inner membrane is not permeable to NADH, how can the NADH generated by glycolysis in the cytosol be reoxidized to NAD+ by O2 via the respiratory chain? Special shuttle systems carry reducing equivalents from cytosolic NADH into mitochondria by an indirect route. The most active NADH shuttle, which functions in liver, kidney, and heart mitochondria, is the malate-aspartate shuttle (Fig. 19–27). The reducing equivalents of cytosolic NADH are first transferred to cytosolic oxaloacetate to yield malate, catalyzed by cytosolic malate dehydroge nase. The malate thus formed passes through the inner membrane via the malate–α-ketoglutarate transporter. Within the matrix the reducing equivalents are passed to NAD+ by the action of matrix malate dehydrogenase, forming NADH; this NADH can pass electrons directly to the respiratory chain. About 2.5 molecules of ATP are generated as this pair of electrons passes to O2. Cytosolic oxaloacetate must be regenerated by transamination reactions and the activity of membrane trans porters to start another cycle of the shuttle. Skeletal muscle and brain use a different NADH shuttle, the glycerol 3-phosphate shuttle (Fig. 19–28). It differs from the malate-aspartate shuttle in that it delivers the reducing equivalents from NADH to ubiquinone and thus into Complex III, not Complex I (Fig. 19–8), providing only enough energy to synthesize 1.5 ATP molecules per pair of electrons. The mitochondria of plants have an externally oriented NADH dehydrogenase that can transfer electrons directly from cytosolic NADH into the respiratory chain at the level of ubiquinone. Because this pathway by passes the NADH dehydrogenase of Complex I and the associated proton movement, the yield of ATP from cytosolic NADH is less than that from NADH generated in the matrix (Box 19–1).
FIGURE 19–27 Malate-aspartate shuttle. This shuttle for transporting reducing equivalents from cytosolic NADH into the mitochondrial matrix is used in liver, kidney, and heart. 1 NADH in the cytosol (intermembrane space) passes two reducing equivalents to oxaloacetate, producing malate. 2 Malate crosses the inner membrane via the malate–-ketoglutarate transporter. 3 In the matrix, malate passes two reducing equivalents to NAD+, and the resulting NADH is oxidized by the respiratory chain. The oxaloacetate formed from malate cannot pass directly into the cytosol. 4 It is first transaminated to aspartate, which 5 can leave via the glutamate-aspartate transporter. 6 Oxaloacetate is regenerated in the cytosol, completing the cycle.
FIGURE 19–28 Glycerol 3-phosphate shuttle. This alternative means of moving reducing equivalents from the cytosol to the mitochondrial matrix operates in skeletal muscle and the brain. In the cytosol, dihydroxyacetone phosphate accepts two reducing equivalents from NADH in a reaction catalyzed by cytosolic glycerol 3-phosphate dehydrogenase. An isozyme of glycerol 3-phosphate dehydrogenase bound to the outer face of the inner membrane then transfers two reducing equivalents from glycerol 3-phosphate in the intermembrane space to ubiquinone. Note that this shuttle does not involve membrane transport systems.
