Pyruvic acid mitochondrial transport

Pyruvate derived from glycolysis or from catabolism of certain amino acids is transported from the cytoplasm into the mitochondrial matrix. 

Pyruvate is first transported from the cytosol into mitochondria or is generated from alanine within mitochondria by transamination, in which the a-amino group is removed from alanine (leaving pyruvate) and added to an a-keto carboxylic acid (transamination reactions are discussed in detail in Chapter 18). Then pyruvate carboxylase, a mitochondrial enzyme that requires the coenzyme biotin, converts the pyruvate to oxaloacetate (Fig. 14-17) ... 

COMPARTMENTALIZED PYRUVATE CARBOXYLASE DEPENDS ON METABOLITE CONVERSION AND TRANSPORT The second interesting feature of pyruvate carboxylase is that it is found only in the matrix of the mitochondria. By contrast, the next enzyme in the gluconeogenic pathway, PEP carboxykinase, may be localized in the cytosol or in the mitochondria or both. For example, rabbit liver PEP carboxykinase is predominantly mitochondrial, whereas the rat liver enzyme is strictly cytosolic. In human liver, PEP carboxykinase is found both in the cytosol and in the mitochondria. Pyruvate is transported into the mitochondrial matrix, where it can be converted to acetyl-CoA (for use in the TCA cycle) and then to citrate (for fatty acid synthesis see Figure 25.1). /Uternatively, it may be converted directly to 0/ A by pyruvate carboxylase and used in glu-... 

Succinyl-CoA derived from propionyl-CoA can enter the TCA cycle. Oxidation of succinate to oxaloacetate provides a substrate for glucose synthesis. Thus, although the acetate units produced in /3-oxidation cannot be utilized in glu-coneogenesis by animals, the occasional propionate produced from oxidation of odd-carbon fatty acids can be used for sugar synthesis. Alternatively, succinate introduced to the TCA cycle from odd-carbon fatty acid oxidation may be oxidized to COg. However, all of the 4-carbon intermediates in the TCA cycle are regenerated in the cycle and thus should be viewed as catalytic species. Net consumption of succinyl-CoA thus does not occur directly in the TCA cycle. Rather, the succinyl-CoA generated from /3-oxidation of odd-carbon fatty acids must be converted to pyruvate and then to acetyl-CoA (which is completely oxidized in the TCA cycle). To follow this latter route, succinyl-CoA entering the TCA cycle must be first converted to malate in the usual way, and then transported from the mitochondrial matrix to the cytosol, where it is oxida-... 

The acetyl-CoA derived from amino acid degradation is normally insufficient for fatty acid biosynthesis, and the acetyl-CoA produced by pyruvate dehydrogenase and by fatty acid oxidation cannot cross the mitochondrial membrane to participate directly in fatty acid synthesis. Instead, acetyl-CoA is linked with oxaloacetate to form citrate, which is transported from the mitochondrial matrix to the cytosol (Figure 25.1). Here it can be converted back into acetyl-CoA and oxaloacetate by ATP-citrate lyase. In this manner, mitochondrial acetyl-CoA becomes the substrate for cytosolic fatty acid synthesis. (Oxaloacetate returns to the mitochondria in the form of either pyruvate or malate, which is then reconverted to acetyl-CoA and oxaloacetate, respectively.)... 

Examples of such intra cellular membrane transport mechanisms include the transfer of pyruvate, the symport (exchange) mechanism of ADP and ATP and the malate-oxaloacetate shuttle, all of which operate across the mitochondrial membranes. Compartmentalization also allows the physical separation of metabolically opposed pathways. For example, in eukaryotes, the synthesis of fatty acids (anabolic) occurs in the cytosol whilst [3 oxidation (catabolic) occurs within the mitochondria. 

This three-step process for transferring fatty acids into the mitochondrion—esterification to CoA, transesterification to carnitine followed by transport, and transesterification back to CoA—links two separate pools of coenzyme A and of fatty acyl-CoA, one in the cytosol, the other in mitochondria These pools have different functions. Coenzyme A in the mitochondrial matrix is largely used in oxidative degradation of pyruvate, fatty acids, and some amino acids, whereas cytosolic coenzyme A is used in the biosynthesis of fatty acids (see Fig. 21-10). Fatty acyl-CoA in the cytosolic pool can be used for membrane lipid synthesis or can be moved into the mitochondrial matrix for oxidation and ATP production. Conversion to the carnitine ester commits the fatty acyl moiety to the oxidative fate. 

Whereas a major function of biological membranes is to maintain the status quo by preventing loss of vital materials and entry of harmful substances, membranes must also engage in selective transport processes. Living cells depend on an influx of phosphate and other ions, and of nutrients such as carbohydrates and amino acids. They extrude certain ions, such as Na+, and rid themselves of metabolic end products. How do these ionic or polar species traverse the phospholipid bilayer of the plasma membrane How do pyruvate, malate, the tricarboxylic acid citrate and even ATP move between the cytosol and the mitochondrial matrix (see figs. 13.15 and 14.1) The answer is that biological membranes contain proteins that act as specific transporters, or permeases. These proteins behave much like conventional enzymes They bind substrates and they release products. Their primary function, however, is not to catalyze chemical reactions but to move materials from one side of a membrane to the other. In this section we discuss the general features of membrane transport and examine the structures and activities of several transport proteins. 

Several inherited disorders are associated with faulty operation of the electron transport pathway. ATP production is diminished in such cases. These disorders are known as mitochondrial myopathies, and they are associated with the absence of specific polypeptide chains found in complexes I, III, or IV. In many cases, the problem may be traced to specific lesions in mitochondrial DNA, which codes for at least 13 polypeptide chains found in these complexes. Myopathies are tissue specific some affect the heart, others the skeletal muscle. Many are accompanied by lactic acidosis, because the inability to reduce NADH normally results in its accumulation and the channeling of pyruvate toward lactic acid production. In complex I disorders, the oxidation of FADH2 is not impeded. In complex III lesions, neither NADH nor FADH2 can be oxidized. However, use has been made by B. Chance and colleagues of menadione (Chapter 6) and ascorbic acid in such cases. The former can oxidize UQH2, whereas ascorbate can oxidize menadione and reduce cytochrome c. Marked clinical improvement in affected patients follows such treatment. 

Pyruvate enters the tricarboxylic acid cycle after conversion into acetyl-CoA via the PDHC. The tricarboxylic acid cycle generates NADH from NAD+, and the NADH then enters the mitochondrial electron-transport chain. 

Primary carnitine deficiency is caused by a deficiency in the plasma-membrane carnitine transporter. Intracellular carnitine deficiency impairs the entry of long-chain fatty acids into the mitochondrial matrix. Consequently, long-chain fatty acids are not available for p oxidation and energy production, and the production of ketone bodies (which are used by the brain) is also impaired. Regulation of intramitochondrial free CoA is also affected, with accumulation of acyl-CoA esters in the mitochondria. This in turn affects the pathways of intermediary metabolism that require CoA, for example the TCA cycle, pyruvate oxidation, amino acid metabolism, and mitochondrial and peroxisomal -oxidation. Cardiac muscle is affected by progressive cardiomyopathy (the most common form of presentation), the CNS is affected by encephalopathy caused by hypoketotic hypoglycaemia, and skeletal muscle is affected by myopathy. 

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