Impaired mitochondrial beta-oxidation in a patient with an abnormality of the respiratory chain. Studies in skeletal muscle mitochondria.

Watmough, Nicholas J.; Bindoff, Laurence A.; Birch‐Machin, Mark A.; Jackson, Sandra; Bartlett, K.; Ragan, C I; Poulton, Joanna; Gardiner, R. M.; Sherratt, H. S. A.; Turnbull, D. M.

doi:10.1172/jci114409

Cited by 73 publications

(48 citation statements)

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“…The only intermediates seen in incubations with human fibroblast (15) and muscle (4,24) mitochondria from healthy subjects were saturated acyl-CoA and acylcarnitine esters. Therefore, the production of 3-hydroxyacylcarnitine and 2-enoylcarnitine esters in peripheral blood cells was a surprising finding.…”

Section: Discussionmentioning

confidence: 99%

“…Disturbance of the mitochondrial architecture or inhibition of P-oxidation enzymes by the permeabilization procedure was unlikely to be responsible for the accumulation of these unusual metabolites, because untreated isolated mitochondria from peripheral blood cells gave a similar pattern of intermediates. Moreover, the incubations were performed under conditions identical to those described for muscle (4,24) and fibroblast (15) mitochondria, in which only saturated intermediates are generated. Our preparation of peripheral blood cells contained a mixture of platelets and leukocytes.…”

Section: Discussionmentioning

confidence: 99%

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Fatty Acid Oxidation in Peripheral Blood Cells: Characterization and Use for the Diagnosis of Defects of Fatty Acid Oxidation

et al. 1995

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fatty Acid Oxidation in Peripheral Blood Cells: Characterization and Use for the Diagnosis of Defects of Fatty Acid Oxidation

et al. 1995

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“…The effects of succinate, carnitine and osmolality on the CoA and carnitine esters resulting from P-oxidation were also explored, furthering our previous work on the relationship between P-oxidation and the respiratory chain in rat muscle (Eaton et al, 1993a), human muscle (Watmough et al, 1990) and fibroblast (Singh Kler et al, 1991) mitochondria.…”

mentioning

confidence: 90%

Redox control of β‐oxidation in rat liver mitochondria

Eaton

Turnbull

Bartlett

1994

European Journal of Biochemistry

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Coupled rat liver mitochondria were incubated with [U-i4C]hexadecanoate and carnitine which resulted in the formation of acyl-, 2-enoyl-and 3-hydroxyacyl-CoA and carnitine esters. The production of 2-enoyl-CoA and 3-hydroxyacyl-CoA esters was associated with a significant lowering of the NAD'NADH ratio, in contrast to rat muscle mitochondria [Eaton, S., Bhuiyan, A. K. M. J., Kler, R. S., Turnbull, D. M. & Bartlett, K. (1993) Biochem. J. 289, 161-1721, suggesting that control by the respiratory chain is important under normal conditions. When NAD'NADH ratios were held low by succinate-induced reverse electron flow, 3-enoyl-CoA esters were also detected, probably formed by the action of 3,2-enoyl-CoA isomerase. Measurement of the flux of P-oxidation at different osmolalities showed that flux was strongly dependent on osmolality changes in the physiological range. Measurement of the CoA and carnitine esters resulting from incubations made at different osmolalities showed that there was an increase in the amounts of the saturated acyl-CoA esters with respect to 2-enoyl-CoA and 3-hydroxyacyl-CoA esters, consistent with control by the electron-transfer flavoprotein-ubiquinone segment [Halestrap, A. P. & Dunlop, J. L. (1986) Biochem. J. 239, 559-5651. This however could not be the only factor operating as indicated by the continued presence of 2-enoyl-CoA and 3-hydroxyacyl-CoA esters at high osmolalities.Mitochondria1 P-oxidation is linked to the respiratory chain at two stages ; the 3-hydroxyacyl-CoA dehydrogenases to complex I via NAD'DJADH and the acyl-CoA dehydrogenases to ubiquinone via electron-transfer flavoprotein (ETF) and its oxidoreductase (ETF: QO). Inhibition of respiratory-chain activity at the level of complex I leads to diminished P-oxidation flux and the accumulation of 3-hydroxyacyl-CoA and 2-enoyl-CoA and carnitine esters (Bremer and

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“…Respiratory chain defects are known to cause secondary inhibition of B-oxidation and this may at least partly account for the steatosis observed in liver and muscle (5). It is also easy to envisage energy deficiency leading to cell death, which in turn might lead to other changes, such as fibrosis.…”

Section: Pathogenesis Of Mitochondrial Diseasementioning

confidence: 99%

Mitochondrial respiratory chain disorders and the liver

Morris

1999

Liver

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Mitochondrial respiratory chain disorders are an established cause of liver failure in early childhood but they are probably under-diagnosed, partly due to under-recognition and partly due to the difficulty of investigation. It is particularly important to look for mitochondrial disorders if the liver disease presents with hypoglycaemia and lactic acidaemia or if it is accompanied by neurological, muscle or renal tubular abnormalities. Respiratory chain defects have been demonstrated in a number of patients who die of liver failure following severe epilepsy; this includes at least some cases of Alpers syndrome or 'progressive neuronal degeneration of childhood'. In mitochondrial liver disease, histology usually shows steatosis, often accompanied by fibrosis, cholestasis and loss of hepatocytes. Unless the clinical picture suggests a particular syndrome, such as Pearson syndrome, biochemical assays and histochemistry should be the initial investigations. Ideally, investigations should be carried out on liver as well as more standard tissues, such as muscle, since defects can be tissue-specific. Nuclear defects and nitDNA point mutations are probably responsible for many cases of mitochondrial liver disease but, as yet, the only identified molecular abnormalities are mtDNA rearrangements and mtDNA depletion. Treatment of mitochondrial liver disease is unsatisfactory. If the disease is confined to the liver, transplantation may be appropriate but in several patients transplantation has been followed by the appearance of disease in other organs, particularly the I brain.Mitochondria are subcellular organelles whose primary role is the oxidation of fuels to produce energy. This process is accomplished by a series of enzymes known as the mitochondrial respiratory chain. Mitochondria are the site of many other metabolic pathways but the term 'mitochondrial disease' is generally used to refer to those conditions associated with respiratory chain defects. Since the oxidation of fuels is important for almost all cells, defects of the mitochondrial respiratory chain can cause disease in any organ of the body. Liver disease is a relatively common problem in respiratory chain disorders that present during infancy. These genetic disorders are the sub,ject of the current review. Secondary defects of tlhe respiratory chain caused, for example, by drugs or toxins, can also lead to liver disease but these disorders are only considered briefly in the section on pathogenesis, where key references are giiven. Mitochondrial biochemistryMany oxidative reactions occur within mitochondria, including the D-oxidation pathway for fatty acids, the oxidative decarboxylation of pyruvate by the pyruvate dehydrogenase complex and the oxidation of acetyl-CoA by the tricarboxylic acid cycle. These reactions all generate reduced cofactors, such as the reduced forms of flavin adenine dinucleotide (FADH2) and nicotinamide adenine dinucleotide (NADH). The mitochondrial respiratory chain couples the reoxidation of these cofactors to the for...

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Impaired mitochondrial beta-oxidation in a patient with an abnormality of the respiratory chain. Studies in skeletal muscle mitochondria.

Cited by 73 publications

References 46 publications

Fatty Acid Oxidation in Peripheral Blood Cells: Characterization and Use for the Diagnosis of Defects of Fatty Acid Oxidation

Fatty Acid Oxidation in Peripheral Blood Cells: Characterization and Use for the Diagnosis of Defects of Fatty Acid Oxidation

Redox control of β‐oxidation in rat liver mitochondria

Mitochondrial respiratory chain disorders and the liver

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