Carnitine transporter, plasma membrane

Defects of mitochondrial transport interfere with the movement of molecules across the inner mitochondrial membrane, which is tightly regulated by specific translocation systems. The carnitine cycle is shown in Figure 42-2 and is responsible for the translocation of acyl-CoA thioesters from the cytosol into the mitochondrial matrix. The carnitine cycle involves four elements the plasma membrane carnitine transporter system, CPT I, the carnitine-acyl carnitine translocase system in the inner mitochondrial membrane and CPT II. Genetic defects have been described for each of these four steps, as discussed previously [4,8,9]. 

As many as 1 in 10,000 persons may inherit such prob-lems.48 50a Tire proteins that may be defective include a plasma membrane carnitine transporter carnitine palmitoyltransferases camitine/acylcamitine trans-locase long-chain, medium-chain, and short-chain acyl-CoA dehydrogenases 2,4-dienoyl-CoA reductase (Eq. 17-1) and long-chain 3-hydroxyacyl-CoA dehydrogenase. Some of these are indicated in Fig. 17-2. 

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. 

A) Carnitine transports the fatty acid across the plasma membrane... 

C. Fatty acids cross the inner mitochondrial membrane on a carnitine carrier. This process is inhibited during fatty acid synthesis by malonyl CoA. Fatty acids are very insoluble in water and are transported in the blood by serum albumin. They cross the plasma membrane and are converted to fatty acyl CoA by CoASH and ATP. In the process, ATP is converted to AMP, so fatty acid activation utilizes the equivalent of 2 ATP. In mitochondria, fatty acids are oxidized to C02 and H20. They cannot be oxidized in red blood cells, which lack mitochondria. 

Fig. 23.1. Overview of mitochondrial long-chain fatty acid metabolism. (1) Fatty acid binding proteins (FaBP) transport fatty acids across the plasma membrane and bind them in the cytosol. (2) Fatty acyl CoA synthetase activates fatty acids to fatly acyl CoAs. (3) Carnitine transports the activated fatty acyl group into mitochondria. (4) p-oxidation generates NADH, FAD(2H), and acetyl CoA (5) In the liver, acetyl CoA is converted to ketone bodies...

As Otto Shape runs, his skeletal muscles increase their use of ATP and their rate of fuel oxidation. Fatty acid oxidation is accelerated by the increased rate of the electron transport chain. As ATP is used and AMP increases, an AMP-dependent protein kinase acts to facilitate fuel utilization and maintain ATP homeostasis. Phosphorylation of acetyl CoA carboxylase results in a decreased level of malonyl CoA and increased activity of carnitine palmitoyl CoA transferase I. At the same time, AMP-dependent protein kinase facilitates the recruitment of glucose transporters into the plasma membrane of skeletal muscle, thereby increasing the rate of glucose uptake. AMP and hormonal signals also increase the supply of glucose 6-P from glycogenoly-sis. Thus, his muscles are supplied with more fuel, and all the oxidative pathways are accelerated. 

One of the functions of hepatic P-oxidation is to provide ketone bodies, acetoac-etate and p-hydroxybutyrate, to the peripheral circulation. These can then be utilized by peripheral tissues such as brain and heart. Beta-oxidation itself produces acetyl-CoA which then has three possible fates entry to the Krebs cycle via citrate S5mthase keto-genesis or transesterification to acetyl-carnitine by the action of carnitine acetyltrans-ferase (CAT). Intramitochondrial acetyl-carnitine then equilibrates with plasma via the carnitine acyl-camitine translocase and presumably via the plasma membrane carnitine transporter. Human studies have shown that acetyl-carnitine may provide up to 5% of the circulating carbon product from fatty acids and can be taker and utilized by muscle and possibly brain." In addition, acyl-camitines are of important with regard to the diagnosis of inborn errors of P- oxidation. For these reasons, we wished to examine the production of acetyl-carnitine and other acyl-camitine esters by neonatal rat hepatocytes. 

Primary carnitine deficiency results from a defect in the carnitine transporter within the plasma membrane resulting in the inability to reabsorb carnitine and in significant loss of urinary carnitine. As a result, extremely low serum... 

After transport across the plasma membrane, FAs must be esterified to coenzyme A, on the outer mitochodrial membrane by long chain acyl-CoA synthetase activity (ACSL C12 to C20) before they can undergo oxidative degradation. This reaction is coupled with two ATP hydrolysis to AMP and 2Pi. The mitochondrial membrane is not permeable to long chain acyl-CoA (i.e., C16-C18), therefore requires the initial conversion of acyl-CoA to an ester acylcamitine, followed by transport of the acylcamitine across the inner mitochondrial membrane into the mitochondrial matrix and subsequent delivery of acyl-CoA [126], This process is referred to as carnitine shuttle and requires the concerted action of 3 proteins 6 ... 

Very low plasma total carnitine levels (i.e. <15 pM) with a normal acyl-carnitine pattern could signal any of a number of acquired deficiencies (diet or drug related) or a deficiency of the plasma membrane transporter. Patients with certain metabolic disorders, especially GA-I and fatty acid oxidation disorders such as MCAD and VLCAD, who have never received carnitine supplement can become markedly carnitine deficient, and their acylcarnitine profiles may be interpreted as normal if pathognomonic metabolite levels do not exceed the normal cut-off. Carnitine deficiency or in-... 

The conversion of long-chain fatty acids into ketone bodies is schematically drawn in Fig. 14.1. The whole process takes place in the liver cell. Long-chain fatty acids are taken up by the cell and are converted into co enzyme A esters (AS). Carnitine has to be brought into the cell by its plasma membrane transporter. Once inside the intermembrane space, acyl-CoA and carnitine react under the influence of CPTl, a membrane-bound enzyme, the activity of which is regulated by the levels of malonyl-CoA and glucagon. This is the key regulating step of the fatty acid yff-oxidation. 

Fatty acids released by the lipase are transported out of the cell, bound to plasma albumin (section 5.3.5) and transported to those tissues, such as muscle, that utilize fatty acids as major sources of fuel. Whether fatty acids are directed into /3-oxidation or acylglycerol synthesis may be governed by the competition for available acyl-CoA molecules by the acyltransferases involved in the esterification of acylglycerols (section 4.6.2) and the carnitine palmitoyl transferase of the mitochondrial membrane (Figure 4.14... 

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