Harpers

THE RESPIRATORY CHAIN & OXIDATIVE PHOSPHORYLATION / 99carboxylate anions and amino acids require specifictransporter or carrier systems to facilitate their passageacross the membrane. Monocarboxylic acids penetratemore readily in their undissociated and more lipid-solubleform.The transport of di- and tricarboxylate anions isclosely linked to that of inorganic phosphate, whichpenetrates readily as the H 2 PO 4 − ion in exchange forOH − . The net uptake of malate by the dicarboxylatetransporter requires inorganic phosphate for exchangein the opposite direction. The net uptake of citrate,isocitrate, or cis-aconitate by the tricarboxylate transporterrequires malate in exchange. α-Ketoglutaratetransport also requires an exchange with malate. Theadenine nucleotide transporter allows the exchange ofATP and ADP but not AMP. It is vital in allowingATP exit from mitochondria to the sites of extramitochondrialutilization and in allowing the return of ADPfor ATP production within the mitochondrion (Figure12–11). Na + can be exchanged for H + , driven by theproton gradient. It is believed that active uptake of Ca 2+by mitochondria occurs with a net charge transfer of 1(Ca + uniport), possibly through a Ca 2+ /H + antiport.Calcium release from mitochondria is facilitated by exchangewith Na + .OUTSIDEP i–InnermitochondrialmembraneF 13H + ATP 4–21INSIDEH +ATP SYNTHASEADP 3–Figure 12–11. Combination of phosphate transporter(1 ) with the adenine nucleotide transporter (2 )in ATP synthesis. The H + /P i symport shown is equivalentto the P i /OH − antiport shown in Figure 12–10. Fourprotons are taken into the mitochondrion for each ATPexported. However, one less proton would be taken inwhen ATP is used inside the mitochondrion.Ionophores Permit Specific Cationsto Penetrate MembranesIonophores are lipophilic molecules that complex specificcations and facilitate their transport through biologicmembranes, eg, valinomycin (K + ). The classicuncouplers such as dinitrophenol are, in fact, protonionophores.A Proton-Translocating TranshydrogenaseIs a Source of Intramitochondrial NADPHEnergy-linked transhydrogenase, a protein in the innermitochondrial membrane, couples the passage of protonsdown the electrochemical gradient from outside toinside the mitochondrion with the transfer of H fromintramitochondrial NADH to NADPH for intramitochondrialenzymes such as glutamate dehydrogenaseand hydroxylases involved in steroid synthesis.Oxidation of Extramitochondrial NADHIs Mediated by Substrate ShuttlesNADH cannot penetrate the mitochondrial membrane,but it is produced continuously in the cytosol by3-phosphoglyceraldehyde dehydrogenase, an enzyme inthe glycolysis sequence (Figure 17–2). However, underaerobic conditions, extramitochondrial NADH does notaccumulate and is presumed to be oxidized by the respiratorychain in mitochondria. The transfer of reducingequivalents through the mitochondrial membrane requiressubstrate pairs, linked by suitable dehydrogenaseson each side of the mitochondrial membrane. Themechanism of transfer using the glycerophosphateshuttle is shown in Figure 12–12). Since the mitochondrialenzyme is linked to the respiratory chain via aflavoprotein rather than NAD, only 2 mol rather than3 mol of ATP are formed per atom of oxygen consumed.Although this shuttle is present in some tissues(eg, brain, white muscle), in others (eg, heart muscle) itis deficient. It is therefore believed that the malateshuttle system (Figure 12–13) is of more universalutility. The complexity of this system is due to the impermeabilityof the mitochondrial membrane to oxaloacetate,which must react with glutamate and transaminateto aspartate and α-ketoglutarate before transportthrough the mitochondrial membrane and reconstitutionto oxaloacetate in the cytosol.Ion Transport in MitochondriaIs Energy-LinkedMitochondria maintain or accumulate cations such asK + , Na + , Ca 2+ , and Mg 2+ , and P i . It is assumed that aprimary proton pump drives cation exchange.