Exchange diffusion systems involving transporter proteins that span the membrane are present in the membrane for exchange of anions against OH⁻ ions and cations against H⁺ ions. Such systems are necessary for uptake and output of ionized metabolites while preserving electrical and osmotic equilibrium. The inner mitochondrial membrane is freely permeable to uncharged small molecules, such as oxygen, water, CO₂ , NH₃ , and to mono carboxylic acids, such as 3-hydroxybutyric, acetoacetic, and acetic, especially in their undissociated, more lipid soluble form. Long-chain fatty acids are transported into mitochondria via the carnitine system , and there is also a special carrier for pyruvate involving a symport that utilizes the H⁺ gradient from outside to inside the mitochondrion . However, dicarboxylate and tricarboxylate anions (eg, malate, citrate) and amino acids require specific transporter or carrier systems to facilitate their passage across the membrane.

The transport of di- and tricarboxylate anions is closely linked to that of inorganic phosphate, which penetrates readily as the H₂PO₄ ⁻ ion in exchange for OH⁻. The net uptake of malate by the dicarboxylate transporter requires inorganic phosphate for exchange in the opposite direction. The net uptake of citrate, isocitrate, or cis-aconitate by the tricarboxylate transporter requires malate in exchange. α-Ketoglutarate transport also requires an exchange with malate. The adenine nucleotide transporter allows the exchange of ATP and ADP, but not AMP. It is vital for ATP to exit from mitochondria to the sites of extramitochondrial utilization and for the return of ADP for ATP production within the mitochondrion (Figure1). Since in this translocation four negative charges are removed from the matrix for every three taken in, the electrochemical gradient across the membrane (the proton motive force) favors the export of ATP. Na⁺ can be exchanged for H⁺, driven by the proton gradient. It is believed that active uptake of Ca²⁺ 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 exchange with Na⁺.

Fig1. Combination of phosphate transporter with the adenine nucleotide transporter in ATP synthesis .The H⁺/Pi symport shown is equivalent to the Pi /OH−antiport.

Ionophores Permit Specific Cations to Penetrate Membranes

 Ionophores are lipophilic molecules that complex specific cations and facilitate their transport through biologic mem branes, for example, valinomycin (K+). The classic uncouplers such as dinitrophenol are, in fact, proton ionophores.

 Proton-Translocating Transhydrogenase Is a Source of Intramitochondrial NADPH

Proton-translocating transhydrogenase (also called NAD(P) transhydrogenase), a protein in the inner mitochondrial mem brane, couples the passage of protons down the electrochemical gradient from outside to inside the mitochondrion with the transfer of H from intramitochondrial NADH to NADP forming NADPH for intramitochondrial enzymes such as glutamate dehydrogenase and hydroxylases involved in steroid synthesis.

 Oxidation of Extramitochondrial NADH Is Mediated by Substrate Shuttles

 NADH cannot penetrate the mitochondrial membrane, but it is produced continuously in the cytosol by glyceraldehyde 3-phosphate dehydrogenase, an enzyme in the glycolysis sequence . However, under aerobic conditions, extramitochondrial NADH does not accumulate and is presumed to be oxidized by the respiratory chain in mitochondria. The transfer of reducing equivalents through the mitochondrial membrane requires substrate pairs, linked by suitable dehydrogenases on each side of the mitochondrial membrane. The mechanism of transfer using the glycerophosphate shuttleis shown in Figure 2. Since the mitochondrial enzyme is linked to the respiratory chain via a flavoprotein rather than NAD, only 1.5 mol rather than 2.5 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) it is deficient. It is therefore believed that the malate shuttle system (Figure 3) is of more universal utility. The complexity of this system is due to the impermeability of the mitochondrial membrane to oxaloacetate. This is overcome by a transamination reaction with glutamate forming aspartate and α-ketoglutarate which can then cross the membrane via specific transporters and reform oxaloacetate in the cytosol.

Fig2. Glycerophosphate shuttle for transfer of reducing equivalents from the cytosol into the mitochondrion.

Fig3. Malate shuttle for transfer of reducing equivalents from the cytosol into the mitochondrion. α-Ketoglutarate trans porter and glutamate/aspartate transporter (note the proton symport with glutamate). α-KG, α-ketoglutarate. NAD+is generated from NADH outside the mitochondrion via the formation of malate from oxaloacetate. Malate crossed the inner membrane in exchange for α-KG and is converted back to oxaloacetate, releasing NADH inside the matrix. (Asp) and α-KG are then produced from oxaloacetate and glutamate by a transaminase enzyme and are transported into the cytosol, where oxaloacetate is reformed by a second transaminase and may be used to generate another NAD+ from NADH.

The Creatine Phosphate Shuttle Facilitates Transport of High-Energy Phosphate From Mitochondria

The creatine phosphate shuttle (Figure 4) augments the functions of creatine phosphate as an energy buffer by acting as a dynamic system for transfer of high-energy phosphate from mitochondria in active tissues such as heart and skeletal muscle. An isoenzyme of creatine kinase (CKm ) is found in the mitochondrial intermembrane space, catalyzing the transfer of high-energy phosphate to creatine from ATP emerging from the adenine nucleotide transporter. In turn, the creatine phosphate is transported into the cytosol via protein pores in the outer mitochondrial membrane, becoming available for generation of extramitochondrial ATP.

Fig4. The creatine phosphate shuttle of heart and skeletal muscle .The shuttle allows rapid transport of high-energy phosphate from the mitochondrial matrix into the cytosol. (CK_a , creatine kinase concerned with large requirements for ATP, eg, muscular contraction; CK_c , creatine kinase for maintaining equilibrium between creatine and creatine phosphate and ATP/ADP; CKg , creatine kinase coupling glycolysis to creatine phosphate synthesis; CKm , mitochondrial creatine kinase mediating creatine phosphate production from ATP formed in oxidative phosphorylation; P, pore protein in outer mitochondrial membrane.)

مواضيع ذات صلة

Overview of Substrate Metabolism in Fasting & Feasting

Many Poisons Inhibit the Respiratory Chain

The Respiratory Chain Provides Most Of The Energy Captured During Catabolism

Electron Transport Via The Respiratory Chain Creates A Proton Gradient Which Drives The Synthesis of ATP

The Respiratory Chain Oxidizes Reducing Equivalents & Acts as A Proton Pump

دورة الخلية وتخليق الدنا Cell Cycle & DNA Synthesis

Oxygenases Catalyze The Direct Transfer & Incorporation of Oxygen Into A Substrate Molecule

Hydroperoxidases Use Hydrogen Peroxide or an Organic Peroxide as Substrate

اضطرابات استقلاب النوكليوتيدات البيريميدينية

اضطرابات استقلاب النكليوتيدات البورينية

تخليق النوكليوتيدات منقوصة الاكسجين ( dNTPs )

تقويض النوكليوتيدات البيريميدينية