Mitochondria fatty acids oxidation

Oxidation of ingested alcohol produces acetaldehyde, acetate, and NADH. A high NADH/NAD+ ratio slows the TCA cycle and promotes the synthesis of glycerol 3-phosphate from dihydroxyacetone phosphate. Fatty acid synthesis is stimulated and, because of the effects of ethanol on mitochondria, fatty acid oxidation is decreased. The net result is that fatty acids react... 

Glucose is the only fuel used by red blood cells, because they lack mitochondria. Fatty acid oxidation, amino acid oxidation, the TCA cycle, the electron transport chain, and oxidative phosphorylation (ATP generation that is dependent on oxygen... 

Fatty acid uptake into cardiac muscle is similar to that for other muscle cell types and requires fatty acid-binding proteins and carnitine palmitoyl transferase I for transfer into the mitochondria. Fatty acid oxidation in cardiac muscle cells is regulated by altering the activities of ACC-2 and malonyl CoA decarboxylase. 

The processes of electron transport and oxidative phosphorylation are membrane-associated. Bacteria are the simplest life form, and bacterial cells typically consist of a single cellular compartment surrounded by a plasma membrane and a more rigid cell wall. In such a system, the conversion of energy from NADH and [FADHg] to the energy of ATP via electron transport and oxidative phosphorylation is carried out at (and across) the plasma membrane. In eukaryotic cells, electron transport and oxidative phosphorylation are localized in mitochondria, which are also the sites of TCA cycle activity and (as we shall see in Chapter 24) fatty acid oxidation. Mammalian cells contain from 800 to 2500 mitochondria other types of cells may have as few as one or two or as many as half a million mitochondria. Human erythrocytes, whose purpose is simply to transport oxygen to tissues, contain no mitochondria at all. The typical mitochondrion is about 0.5 0.3 microns in diameter and from 0.5 micron to several microns long its overall shape is sensitive to metabolic conditions in the cell. 

T12. Fatty Acid Oxidation in Uncontrolled Diabetes When the acetyl-CoA produced during /3 oxidation in the liver exceeds the capacity of the citric acid cycle, the excess acetyl-CoA forms ketone bodies—acetone, acetoacetate, and D-/3-hydroxybutyrate. This occurs in severe, uncontrolled diabetes because the tissues cannot use glucose, they oxidize large amounts of fatty acids instead. Although acetyl-CoA is not toxic, the mitochondrion must divert the acetyl-CoA to ketone bodies. What problem would arise if acetyl-CoA were not converted to ketone bodies How does the diversion to ketone bodies solve the problem ... 

These organelles are the sites of energy production of aerobic cells and contain the enzymes of the tricarboxylic acid cycle, the respiratory chain, and the fatty acid oxidation system. The mitochondrion is bounded by a pair of specialized membranes that define the separate mitochondrial compartments, the internal matrix space and an intermembrane space. Molecules of 10,000 daltons or less can penetrate the outer membrane, but most of these molecules cannot pass the selectively permeable inner membrane. By a series of infoldings, the internal membrane forms cristae in the matrix space. The components of the respiratory chain and the enzyme complex that makes ATP are embedded in the inner membrane as well as a number of transport proteins that make it selectively permeable to small molecules that are metabolized by the enzymes in the matrix space. Matrix enzymes include those of the tricarboxylic acid cycle, the fatty acid oxidation system, and others. 

The mitochondrion, in addition to being the powerhouse of the cell (because it generates more than 90% of the ATP used by the cell), is also the site of fatty acid oxidation, the tricarboxylic acid (TCA) cycle, electron transport, and amino acid metabolism. Central to the utilization of fuel molecules—carbohydrates, pro-... 

Supplementing the diet with carnitine may stimulate the uptake of long-chain fatty acids into affected cells. Fatty acid oxidation within the mitochondrion will generate acetyl-CoA, which when oxidized in the TCA cycle will produce NADH and FADH2 to feed into the ETC. Carnitine also shuttles potentially toxic fatty acid catabolic by-products out of the mitochondrial matrix to the kidney for excretion in the urine. 

The study described in Figure 4.54 illustrates the role of cytosolic malonyl-CoA in controlling the entry of fatty acids into the mitochondrion. The activity of carnitine acyltransferasc w as measured after adding various concentrations of fatty acyl-CoA (0-250 jiM) to a suspension of mitochondria both w ith and without malonyl-CoA. Transferase activity increased with increasing concentrations of fatty acyl-CoA until a plateau was reached. At this point, the transferase was saturated and unable to operate at a faster rate when presented w ith higher concentrations of its substrate. The activity of the transferase w as impaired in the presence of malonyl-CoA. This indicates that an increase in the rate of fatty acid synthesis, with the resultant increase in concentration of malonyl oA, will impair the oxidation of fatty acids. Therefore, the pathways of fatty acid oxidation and synthesis are coordinated. Figure 4-54 also indicates that malonyl-CoA inhibition can be overcome by higher levels of fatty acy)-CoA. Other studies have revealed... 

In muscle, most of the fatty acids undergoing beta oxidation are completely oxidized to C02 and water. In liver, however, there is another major fate for fatty acids this is the formation of ketone bodies, namely acetoacetate and b-hydroxybutyrate. The fatty acids must be transported into the mitochondrion for normal beta oxidation. This may be a limiting factor for beta oxidation in many tissues and ketone-body formation in the liver. The extramitochondrial fatty-acyl portion of fatty-acyl CoA can be transferred across the outer mitochondrial membrane to carnitine by carnitine palmitoyltransferase I (CPTI). This enzyme is located on the inner side of the outer mitochondrial membrane. The acylcarnitine is now located in mitochondrial intermembrane space. The fatty-acid portion of acylcarnitine is then transported across the inner mitochondrial membrane to coenzyme A to form fatty-acyl CoA in the mitochondrial matrix. This translocation is catalyzed by carnitine palmitoyltransferase II (CPTII Fig. 14.1), located on the inner side of the inner membrane. This later translocation is also facilitated by camitine-acylcamitine translocase, located in the inner mitochondrial membrane. The CPTI is inhibited by malonyl CoA, an intermediate of fatty-acid synthesis (see Chapter 15). This inhibition occurs in all tissues that oxidize fatty acids. The level of malonyl CoA varies among tissues and with various nutritional and hormonal conditions. The sensitivity of CPTI to malonyl CoA also varies among tissues and with nutritional and hormonal conditions, even within a given tissue. Thus, fatty-acid oxidation may be controlled by the activity and relative inhibition of CPTI. 

The control of fatty-acid oxidation is related to the availability of circulating fatty acids and the activity of palmitoyl carnitine transferase 1. When circulating fatty acids are elevated, considerable fatty-acyl CoA is formed in a number of tissues, including the liver, which is sufficient to inhibit both acetyl CoA carboxylase in the cytosol and, indirectly, pyruvate dehydrogenase in the mitochondrion. Under this condition, neither malonyl CoA nor citrate would accumulate thus, there would be a diminution of fatty-acid synthesis. When large amounts of fatty... 

When large amounts of exogenous fatty acid enter the liver, how can they be transferred into the mitochondrion, for beta oxidation, with malonyl CoA inhibition This dichotomy is overcome because fatty-acyl CoAs inhibit acetyl CoA carboxylase and the malonyl CoA present proceeds onto fatty acids. When the malonyl CoA is converted to fatty acid, the level of malonyl CoA drops and is not restored. Thus, the inhibition of acyl carnitine transferase 1 is removed and fatty-acid oxidation can proceed. 

The mitochondria are aerobic cell organelles that are responsible for most of the ATP production in eukaryotic cells. They are enclosed by a double membrane. The outer membrane permits low-molecular-weight molecules to pass through. The inner mitochondrial membrane, by contrast, is almost completely impermeable to most molecules. The inner mitochondrial membrane is the site where oxidative phosphorylation occurs. The enzymes of the citric acid cycle, of amino acid catabolism, and of fatty acid oxidation are located in the matrix space of the mitochondrion. 

Fig. 31.5. Conversion of pyruvate to phosphoenolpyruvate (PEP). Follow the shaded circled numbers on the diagram, starting with the precursors alanine and lactate. The first step is the conversion of alanine and lactate to pyruvate. Pyruvate then enters the mitochondria and is converted to OAA (circle 2) by pyruvate carboxylase. Pyruvate dehydrogenase has been inactivated by both the NADH and acetyl-CoA generated from fatty acid oxidation, which allows oxaloacetate production for gluconeogenesis. The oxaloacetate formed in the mitochondria is converted to either malate or aspartate to enter the cytoplasm via the malate/aspartate shuttle. Once in the cytoplasm the malate or aspartate is converted back into oxaloacetate (circle 3), and phosphoenolpyruvate carboxykinase will convert it to PEP (circle 4). The white circled numbers are alternate routes for exit of carbon from the mitochondrion using the malate/aspartate shuttle. OAA = oxaloacetate FA = fatty acid TG = triacylglycerol.

The oxidation reactions involved are catalyzed by a series of nicotinamide adenine dinucleotide (NAD+) or flavin adenine dinucleotide (FAD) dependent dehydrogenases in the highly conserved metabolic pathways of glycolysis, fatty acid oxidation and the tricarboxylic acid cycle, the latter two of which are localized to the mitochondrion, as is the bulk of coupled ATP synthesis. Reoxidation of the reduced cofactors (NADH and FADH2) requires molecular oxygen and is carried out by protein complexes integral to the inner mitochondrial membrane, collectively known as the respiratory, electron transport, or cytochrome, chain. Ubiquinone (UQ), and the small soluble protein cytochrome c, act as carriers of electrons between the complexes (Fig. 13.1.1). 

The 3-thia, non-P-oxidable thia fatty acids (as exemplified by TTA (tetradecylth-ioacetic acid, HOOC-CH2-S-CH2(13)-CH3) decrease plasma triglycerides and cholesterol levels when administered to rats. At the same time TTA increased the hepatic fatty acid oxidation capacities. Recently we have demonstrated that stimulation of mitochondrial P-oxidation, but not peroxisomal fatty acid oxidation, decreases hepatic triglyceride formation. This has also been shown with co-3 fatty acids and fibrates in different animal models (rats, rabbits and dogs). Altogether the mitochondrion seems to be the principal target for the plasma triglycerid lowering effect. 

The electrons freed during the oxidation of fatty acids or of the Krebs cycle metabolites are ultimately transferred to the electron transport chain. This transfer can best be achieved if the oxidizing system and the electron transport chain are maintained in close contact in their cellular structures. It is therefore not surprising that, with few exceptions, all the enzymes of the fatty acid oxidation pathway are found in mitochondria. It has not yet been possible to reconstruct the exact pattern of the integration of each of these enzymes within the mitochondrial structure. Available information suggests only that these enzymes are not freely soluble within the mitochondrion. However, they are not as tightly bound to the mitochondrial structure as the enzymes of the electron transport chain. 

Mitochondrion A subceUular organelle which contains the enzymes of the citric acid cycle, fatty acid oxidation and the electron transport chain for oxidative phosphorylation of ADP to ATE... 

The reconstruction of fatty acid oxidation has progressed in four distinct phases The study of the process in (1) the whole animal, (2) the tissue slice, (3) the mitochondrion, and finally, (4) a system of soluble enz3rmes. The complexity of the process was too great to make the transi-Lohmann, K., and Schuster, P., Biochem. Z. 294, 188 (1937). 

FIGURE 15.2 Transportation of palmitoyl-CoA into the mitochondrion for fatty acid oxidation... 

Mitochondria are the focus of one of the most intensive research efforts in all of biochemistry, owing to the essential metabolic processes they carry on (the citric acid cycle, fatty acid oxidation, and electron transport are but a few) and most particularly to the nature of the process of oxidative phosphorylation. Table 3 lists the major metabolic pathways and processes that occur within the confines of the mitochondrion. A complete list of enzymes associated with mitochondria is available (Altman and Katz, 1976), as is a review on methods of preparation (Sottocasa, 1976). 

Pathways are compartmentalized within the cell. Glycolysis, glycogenesis, glycogenolysis, the pentose phosphate pathway, and fipogenesis occur in the cytosol. The mitochondrion contains the enzymes of the citric acid cycle, P-oxidation of fatty acids, and of oxidative phosphorylation. The endoplasmic reticulum also contains the enzymes for many other processes, including protein synthesis, glycerofipid formation, and dmg metabolism. 

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