Fatty acid oxidation in mitochondria

Although fatty acids are both oxidized to acetyl-CoA and synthesized from acetyl-CoA, fatty acid oxidation is not the simple reverse of fatty acid biosynthesis but an entirely different process taking place in a separate compartment of the cell. The separation of fatty acid oxidation in mitochondria from biosynthesis in the cytosol allows each process to be individually controlled and integrated with tissue requirements. Each step in fatty acid oxidation involves acyl-CoA derivatives catalyzed by separate enzymes, utihzes NAD and FAD as coenzymes, and generates ATP. It is an aerobic process, requiring the presence of oxygen. 

Fatty acid oxidation in mitochondria leads to the generation of large quantities of ATP by a process called P Oxidation that cleaves acetyl-CoA units sequentially from fatty acyl chains. The acetyl-CoA is oxidized in the citric acid cycle, generating further ATP. 

We begin this chapter with a brief discussion of the sources of fatty acids and the routes by which they travel to the site of their oxidation, with special emphasis on the process in vertebrates. We then describe the chemical steps of fatty acid oxidation in mitochondria The complete oxidation of fatty acids to C02 and H20 takes place in three stages the oxidation of long-chain fatty acids to two-carbon fragments, in the form of acetyl-CoA (/3 oxidation) the oxidation of acetyl-CoA to C02 in the citric acid cycle (Chapter 16) and the transfer of... 

Fatty acid oxidation in mitochondria is diminished when fatty acid biosynthesis in the cytosol is active due to the inhibition of carnitine acyltransferase 1 by malonyl CoA. The synthesis of HMG CoA reductase in various cells is inhibited by low-density... 

When measuring the mitochondrial P-oxidation in liver, 2-methyl EPA did not cause any effect compared to EPA or control, while the other EPA-derivatives increased the fatty acid oxidation in mitochondria. We measured the mitochondrial activity and gene expression of an enzyme involved in the oxidation of unsaturated fatty acids, the 2,4-dienoyl-CoA reductase. Both the activity and gene expression seemed to increase in rats fed 2,2-dimethyl EPA. We also measured the total activity of CPT in liver, and found an increased activity in rats fed 2,2-dimethyl EPA. The increase in total CPT-activity after administration of 2,2-dimethyl EPA seemed to be due to the observed increase in CPT-II transcription, as the mRNA level of CPT-I was unchanged (data to be published). The peroxisomal P-oxidation, the activity and gene e q)ression of fatty acyl-CoA oxidase, the rate-limiting enzyme of peroxisomal P-oxidation, and the gene expression of the peroxisomal multifunctional protein were increased after administration of the EPA-derivatives, as shown in Table 2. 

Table 2. Effect of dietary EPA, DHA and palmitic acid on serum triglycerides and fatty acid oxidation in mitochondria and peroxisomes.

The five biotin-dependent mammalian carboxylases are acetyl-CoA carboxylase isoforms I and II (also known as a-ACC (EC 6.4.1.2) and /3-ACC (EC 6.4.1.2)), pyruvate carboxylase (EC 6.4.1.1), methyl-crotonyl-CoA carboxylase (EC 6.4.1.4), and propio-nyl-CoA carboxylase (EC 6.4.1.3). ACC catalyzes the incorporation of bicarbonate into acetyl-CoA to form malonyl-CoA (Figure 2). There are two isoforms of ACC. Isoform I is located in the cytosol and produces malonyl-CoA, which is rate limiting in fatty acid synthesis (elongation). Isoform II is located on the outer mitochondrial membrane and controls fatty acid oxidation in mitochondria through the inhibitory effect of malonyl-CoA on fatty acid transport... 

The enzymes of fatty acid oxidation in animal cells are located in the mitochondrial matrix, as demonstrated in 1948 by Eugene P. Kennedy and Albert Lehninger. The fatty acids with chain lengths of 12 or fewer carbons enter mitochondria without the help of membrane transporters. Those with 14 or more carbons, which constitute the majority of the FFA obtained in the diet or released from adipose tissue, cannot pass directly through the mitochondrial membranes—they must first undergo the three enzymatic reactions of the carnitine shuttle. The first reaction is catalyzed by a family of isozymes (different isozymes specific for fatty acids having short, intermediate, or long carbon chains) present... 

The mitochondrial matrix is the major site of fatty acid oxidation in animal cells, but in certain cells other compartments also contain enzymes capable of oxidizing fatty acids to acetyl-CoA, by a pathway similar to, but not identical with, that in mitochondria In plant cells, the major site of /3 oxidation is not mitochondria but peroxisomes. 

The Oxidation of Saturated Fatty Acids Occurs in Mitochondria... 

Ganning AE, Olsson MJ, Peterson E, et al. 1989. Fatty acid oxidation in hepatic peroxisomes and mitochondria after treatment of rats with di(2-ethylhexyl)phthalate. Pharmacol Toxicol 65 265-268. 

Answer Malonyl-CoA would no longer inhibit fatty acid entry into the mitochondrion and jS oxidation, so there might be a futile cycle of simultaneous fatty acid synthesis in the cytosol and fatty acid breakdown in mitochondria. (See Fig. 17-12.)... 

D. Oxidation of fatty acids occurs in mitochondria. Red blood cells lack mitochondria and therefore cannot use fatty acids. 

One molecule of oxygen accepts two pairs of electrons, one from palmitoyl-CoA and the other from NADPH or NADH. The electrons NAD(P)H are transported via cytochrome-bs reductase to cytochrome bs (microsomal electron transport Chapter 14). An enzyme-bound superoxide radical is responsible for the oxidation of acyl-CoA. Four desaturases specific for introducing cis double bonds at C9, Ca, C5, and C4, respectively, are known. If the substrate is saturated, the first double bond introduced is C9. With an unsaturated substrate, other double bonds are introduced between the carboxyl group and the double bond nearest the carboxyl group. Desaturation yields a divinylmethane arrangement of double bonds (—CH=CH—CH2—CH=CH—). Usually desaturation alternates with chain elongation. Desaturation is inhibited by fasting and diabetes. The oxidation of unsaturated fatty acids occurs in mitochondria. 

In the neonate, neural NE promotes nonshivering thermogenesis, i.e., heat production via stimulation of lipolysis and fatty acid oxidation in brown adipose tissue ( 63) with the support of thyroid hormone. Brown adipose tissue contains a high density of mitochondria with an uncoupling protein that allows the cells to oxidize fatty acids and generate heat as a major product NE released at nerve endings stimulates cAMP-mediated lipolysis in these cells and promotes thermogenesis by this y83-mechanism (Chapter 14). 

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. 

Bremer, J. Wojtczak, A.B. ( 912) Biochim. Biophys. Acta. 280, 515-530. Factors controlling the rate of fatty acid oxidation in rat liver mitochondria. 

Evidence so far indicates that substrate and cofactor availability, and product inhibition, constitute the main modes for the regulation of fatty acid oxidation within mitochondria there is nothing to indicate that substrate flow over the p-oxidation spiral is further regulated by allosteric or covalent modification of the activity of any enzyme of this spiral. As is to be expected for a multistep metabolic pathway, diverse steps contribute to the overall regulation of fatty acid oxidation in different tissues under different conditions. /S/lore is known about this process in liver and heart than in other tissues and its brief description follows. 

Recently Drysdale has described a soluble enzyme system from rat liver mitochondria which oxidizes fatty acids to acetoacetate. CoA is required for this system. Likewise Green et have observed a CoA-dependent fatty acid oxidation in a soluble preparation from heart muscle. It seems likely, therefore, that the fatty acids undergo /3 oxidation while attached to CoA as an acyl-CoA and that in the complete oxidation of fatty acid acetyl-CoA derived from the /3 oxidation is fed into the tricarboxylic acid cycle by means of the condensing enzyme of Stern and Ochoa. 

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