Mitochondrial P-oxidation of fatty acids

Mitochondrial P oxidation of fatty acids is the principal source of energy for the heart. Consequently, inherited defects of fatty acid oxidation or of carnitine-assisted transport often appear as serious heart disease (inherited cardiomyopathy). These may involve heart failure, pulmonary edema, or sudden infant death. 

Freneaux E, Fromenty B, Berson A, Labbe G, Degott C, Letteron P, Larrey D, Pessayre D (1990) Stereoselective and nonstereoselective effects of ibuprofen enantiomers on mitochondrial P-oxidation of fatty acids. J Pharmacol Exp Ther 255 529-535... 

Mammalian mitochondrial P-oxidation of fatty acids, the process by which fatty acids are oxidized, provides the primary source of energy for die heart and skeletal muscle. In hver, when blood glucose levels are low, the capacity for fatty add P-oxidation... 

A 55-year-old woman developed severe cholestatic liver injury and lactic acidosis after receiving linezolid for 50 days for an infected prosthetic hip [92" ]. Liver biopsy showed Effuse microvesicular steatosis, a mononuclear infiltrate, and bile duct damage. The hepatotoxicity resolved over 14 weeks. Microvesicular steatosis relates to impaired mitochondrial P-oxidation of fatty acids and the authors suggested that UnezoUd may have inhibited mitochondrial protein synthesis. 

Fatty acid -oxidation. Designation of biochemical pathways through which fatty acids are metabolized, resulting in energy production as their oxidation is a highly exergonic process. In mammals, mitochondrial p-oxidation of fatty acid provides a major source of ATP for the heart and skeletal muscle. 

The acetyl-CoA that supplies the cycle with acetyl residues is mainly derived from p-oxidation of fatty acids (see p. 164) and from the pyruvate dehydrogenase reaction. Both of these processes take place in the mitochondrial matrix. 

Carnitine deficiency complicates HMG-CoA lyase deficiency and other inborn errors of metabolism, which results in organic acidemia. L-Camitine or P-hydroxy-y-trimethylammonium butyrate is a carrier molecule that transports long-chain fatty acids across the inner mitochondrial membrane for subsequent P-oxi-dation. L-Carnitine also facilitates removal of toxic metabolic intermediates or xenobiotics via urinary excretion of their acyl carnitine derivatives. Indeed, individuals with HMG-CoA lyase deficiency have been shown to excrete 3-methylgluatarylcamitine (Roe et al., 1986). In the absence of ketogenesis, the formation of the acyl carnitine derivative of 3-hydroxy-3-methylglutarate from HMG-CoA also serves to regenerate free CoA in the mitochondria and permits continued P-oxidation of fatty acids. 

The P-oxidation of fatty acids that occurs in the mitochondrial matrix provides the energy for gluconeogenesis in the liver. Fatty acids transported from adipose tissues by blood albumin cross the hepatic plasma membrane and... 

The enzymes that catalyze the p-oxidation of fatty acids are located in the matrix space of the mitochondria. Special transport mechanisms are required to bring fatty acid molecules into the mitochondrial matrix. Once inside, the fatty acids are degraded by the reactions of p-oxidation. As we will see, these reactions interact with oxidative phosphorylation and the citric acid cycle to produce ATP. 

Fig. 3. Oxidative metabolism in mitochondria. The inner mitochondrial membrane forms infoldings, called cristae, which enclose the mitochondrial matrix. Most of the enzymes for the TCA cycle, the P-oxidation of fatty acids, and for mitochondrial DNA synthesis are found in the matrix. ATP synthase and the protein complexes of the electron transport chain are embedded in the inner mitochondrial membrane. The outer mitochondrial membrane is permeable to small ions, but the inner mitochondrial membrane is impermeable.

No effects in isolated mitochondrial preparations on state 4 respiration, ADP-stimulated or 2,4-dinitrophenol-stimulated respiration, the respiratory control ratio, the adenosine diphosphate/oxygen ratio, the rate of calcium-induced mitochondrial swelling at 50 pM. Loss of MMP was seen rally at the highest concentration of ximelagatrtm tested, 300 pM, in mitochondria exposed for 24 h. No effects on P-oxidation of fatty acids up to 300 pM... 

Rapid p-oxidation of fatty acids in perfused liver (DeBeer et a/., 1974) and in isolated mitochondria (Lopes-Cardozo and Van den Bergh, 1972) has been shown to suppress the operation of citric acid cycle apparently from the elevation of mitochondrial NADH/NAD ratio which restricts oxaloaceta-te availability for citrate synthase and simultaneously inhibits isocitrate oxidation (Lenartowicz et a/., 1976). Considerable support for an earlier postulate that oxaloacetate availability normally determines the rate of citrate synthesis has become available. Thus, because of marked protein binding, the concentration of free, as opposed to total, oxaloacetate in matrix of liver mitochondria is now estimated to be near the of citrate synthase (Siess et al., 1976 Brocks eta ., 1980). The antiketogenic effect of alanine (Nosadini et a/., 1980) and of 3-mercaptopicolinate, an inhibitor of phosphoenolpy-ruvate carboxykinase (Blackshear et a/., 1975), is believed to be exerted, at least in part, from their ability to raise hepatic oxaloacetate concentration. And, in pyruvate carboxylase deficiency, expected to impair oxaloacetate supply, concentration of ketone bodies is elevated (Saudubray et a/., 1976). 

Steatosis (fatty liver) is a metabolic consequence of ethanol abuse. This results from a high mitochondrial ratio of NADH NAD which prevents P-oxidation of fatty acids. 

P-Oxidation of fatty acids is controlled by the uptake of fatty acids into the mitochondria - as discussed in section 5.5.1, this is controlled by the activity of carnitine acyl transferase on the outer mitochondrial membrane, and by the countertransport of acyl-carnitine and free carnitine across the inner mitochondrial membrane. 

Carnitine acyl transferase activity is controlled by malonyl CoA. As discussed in section 10.5.2, in liver and adipose tissue this serves to inhibit mitochondrial uptake and P-oxidation of fatty acids when fatty acids are being synthesized in the cytosol. Muscle also has an active acetyl CoA carboxylase, and synthesizes malonyl CoA, although it does not synthesize fatty acids, and muscle carnitine acyl transferase is more sensitive to inhibition by malonyl CoA than is the enzyme in liver and adipose tissue. 

Unsaturated fatty acids. Mitochondrial P oxidation of such unsaturated acids as the A9-oleic acid begins with removal of two molecules of acetyl-CoA to form a A5-acyl-CoA. However, further metabolism is slow. Two pathways have been identified (Eq. 17-l).26 29b The first step for both is a normal dehydrogenation to a 2-fraus-5-czs-dienoyl-CoA. In pathway I this intermediate reacts slowly by the normal p oxidation sequence to form a 3-czs-enoyl-CoA intermediate which must then be acted upon by an auxiliary enzyme, a ds-AMra s-A2-enoyl-CoA isomerase (Eq. 17-1, step c), before P oxidation can continue. 

P-Oxidation mitochondrial oxidation of fatty acids--> Energy ... 

In animal cells, fatty acids are degraded both in mitochondria and peroxisomes, whereas in lower eukaryotes, P-oxidation is confined to peroxisomes. Mitochondrial P-oxidation provides energy for oxidative phosphorylation and generates acetyl-CoA for ketogenesis in liver. The oxidation of fatty acids with odd numbers of carbon atoms also yields propi-onyl-CoA that is metabolized to succinate. 

Unsaturated fatty acids. Mitochondrial p oxidation of such unsaturated acids as the A -oleic acid begins with removal of two molecules of acetyl-CoA to form a A -acyl-CoA. However, further metabolism is slow. Two pathways have been identified (Eq. 

Freneaux E, Labbe G, Letteron P, Le Dinh T, Degott C, Geneve J, Larrey D, Pessayre D (1988) Inhibition of the mitochondrial oxidation of fatty acids by tetracycline in mice and in man possible role in microvesicular steatosis induced by this antibiotic. Hepatology 8 1056-1062... 

Grimbert S, Fromenty B, Fisch C, Letteron P, Berson A, Durand-Schneider AM, Feldmann G, Pessayre D (1993) Decreased mitochondrial oxidation of fatty acids in pregnant mice possible relevance to development of acute fatty liver of pregnancy. Hepatology 17 628-637... 

Le Dinh T, Freneaux E, Labbe G, Letteron P, Degott C, Geneve J, Berson A, Larrey D, Pessayre D (1988) Amineptine, a tricyclic antidepressant, inhibits the mitochondrial oxidation of fatty acids and produces microvesicular steatosis of the liver in mice. J Pharmacol Exp Ther 247 745-750 Le Roy F, Bisbal C, Silhol M, Martinand C, Lebleu B, Salehzada T (2001) The 2-5A/RNase L/RNase inhibitor (RLl) pathway regulates mitochondrial mRNAs stability in interferon-a-treated H9 cells. J Biol Chem 276 48473 8482 Le Roy F, Silhol M, Salehzada T, Bisbal C (2007) Regulation of mitochondrial mRNA stability by RNase L is translation-dependent and controls IFNalpha-induced apoptosis. Cell Death Differ 14 1406-1413... 

In contrast to CPT-I, the mRNA levels of CPT-II were increased in the long-term as well as in short-term experiments (Fig. 2). These results surest that the regulation of fatty acid oxidation appears to be shifted to steps(s) beyond CPT-I and CPT-II may be an important locus in the regulation of hepatic fatty acid oxidation. The proposed sequence of oxidation of fatty acids involving peroxisomal and mitochondrial P-oxidation under peroxisomal and mitochondrial proliferation is depicted in Fig. 3. A possible explanation would be that fatty acids are partially oxidized in the peroxisomes and enter the mitochondria as medimn chain fatty acids via peroxisomal CPT, like the phy-... 

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