Atp

synthase

Phosphate H PO translocase 2 (symporter)

ATP4

ADP3

Phosphate H PO translocase 2 (symporter)

H4

FIGURE 19-26 Adenine nucleotide and phosphate translocases.

Transport systems of the inner mitochondrial membrane carry ADP and P¡ into the matrix and newly synthesized ATP into the cytosol. The adenine nucleotide translocase is an antiporter; the same protein moves ADP into the matrix and ATP out. The effect of replacing ATP4" with ADP3" is the net efflux of one negative charge, which is favored by the charge difference across the inner membrane (outside positive). At pH 7, P¡ is present as both HPO4" and H2PO"; the phosphate translocase is specific for H2PO". There is no net flow of charge during symport of H2PO" and H+, but the relatively low proton concentration in the matrix favors the inward movement of H + . Thus the proton-motive force is responsible both for providing the energy for ATP synthesis and for transporting substrates (ADP and P¡) in and product (ATP) out of the mitochondrial matrix. All three of these transport systems can be isolated as a single membrane-bound complex (ATP synthasome).

transmembrane electrochemical gradient, which gives the matrix a net negative charge; the proton-motive force drives ATP-ADP exchange. Adenine nucleotide translocase is specifically inhibited by atractyloside, a toxic glycoside formed by a species of thistle. If the transport of ADP into and ATP out of mitochondria is inhibited, cytosolic ATP cannot be regenerated from ADP, explaining the toxicity of atractyloside.

A second membrane transport system essential to oxidative phosphorylation is the phosphate translo-case, which promotes symport of one H2PO44 and one H+ into the matrix. This transport process, too, is favored by the transmembrane proton gradient (Fig. 19-26). Notice that the process requires movement of one proton from the P to the N side of the inner membrane, consuming some of the energy of electron transfer. A complex of the ATP synthase and both translo-cases, the ATP synthasome, can be isolated from mitochondria by gentle dissection with detergents, suggesting that the functions of these three proteins are very tightly integrated.

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 dehydrogenase. The malate thus formed passes through the inner membrane via the malate-a-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. Cy-tosolic oxaloacetate must be regenerated by transamination reactions and the activity of membrane transporters 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 bypasses the NADH dehydrogenase of Complex I and the associated proton movement, the yield of ATP from cy-tosolic NADH is less than that from NADH generated in the matrix (Box 19-1).

SUMMARY 19.2 ATP Synthesis

■ The flow of electrons through Complexes I, III, and IV results in pumping of protons across the inner mitochondrial membrane, making the matrix alkaline relative to the intermembrane space. This proton gradient provides the energy (in the form of the proton-motive force) for ATP synthesis from ADP and Pj by ATP synthase (FoFi complex) in the inner membrane.

Intermembrane space

NAD-

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