Hepatic failure in disorders of oxidative phosphorylation with neonatal onset

Cormier, V.; Rustin, Pierre; Bonnefont, Jean‐Paul; Rambaud, Caroline; Vassault, Anne; Rabier, Daniel; Parvy, P; Couderc, Sophie; Parrot-Roulaud, F.; Carré, Mireille; Risse, Jean-Claude; Cahuzac, C.; Saudubray, Jean‐Marie; Rötig, Agnès; Hubert, Philippe; Münnich, Arnold

doi:10.1016/s0022-3476(05)83054-9

Cited by 58 publications

(18 citation statements)

References 7 publications

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“…COX deficiency is one of the most frequent causes of RC disorders in childhood and is clinically heterogeneous, with phenotypes including encephalomyopathy, Leigh syndrome (33,34), fatal or benign infantile myopathies, liver failure (35), and myoglobinuria. In the past 6 yr, mtDNA mutations have been identified among patients with various clinical presentations.…”

Section: Point Mutations In Mitochondrial Protein Synthesis Genesmentioning

confidence: 99%

Genetic Features of Mitochondrial Respiratory Chain Disorders

Rötig¹,

Münnich²

2003

Journal of the American Society of Nephrology

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Abstract. Oxidative phosphorylation, i.e., ATP synthesis by the oxygen-consuming respiratory chain (RC), supplies most organs and tissues with a readily usable energy source, being functional before birth. Consequently, RC deficiencies can theoretically give rise to any symptom, in any organ or tissue, at any age and with any mode of inheritance, because of the twofold genetic origin of RC components (nuclear DNA and mitochondrial DNA). It was long wrongly considered that RC disorders originate from mutations of mitochondrial DNA, because for a long time only mutations or deletions of mitochondrial DNA were identified. However, the number of known disease-causing mutations in nuclear genes is steadily growing. These genes encode the various subunits of each complex, ancillary proteins functioning at different stages of holoenzyme biogenesis, including transcription, translation, chaperoning, addition of prosthetic groups, and protein assembly, and various enzymes involved in mitochondrial DNA metabolism.The mitochondrial respiratory chain (RC) catalyzes the oxidation of fuel molecules and the concomitant energy transduction into ATP via five complexes, which are embedded in the inner mitochondrial membrane (1) (Figure 1). Complex I [NADHcoenzyme Q (CoQ) reductase] carries reducing equivalents from NADH to CoQ (ubiquinone) and consists of Ͼ40 different polypeptides. Complex II (succinate-CoQ reductase) carries reducing equivalents from FADH 2 to CoQ and contains four polypeptides, including the FAD-dependent succinate dehydrogenase and iron-sulfur proteins. Complex III (reduced CoQ-cytochrome c reductase) carries electrons from CoQ to cytochrome c. It contains 11 subunits. Complex IV [cytochrome c oxidase (COX)], the terminal oxidase of the RC, catalyzes the transfer of reducing equivalents from cytochrome c to molecular oxygen. It is composed of two cytochromes (cytochromes a and a 3 ), two copper atoms, and 13 different protein subunits.During the oxidation process, electrons are transferred to oxygen via the energy-transducing complexes of the RC, i.e., complexes I, III, and IV for NADH-producing substrates; complexes II, III, and IV for succinate; and complexes III and IV for FADH 2 derived from the ␤-oxidation pathway via the electron transfer flavoprotein and the electron transfer flavoprotein-CoQ oxidoreductase system. CoQ, a highly hydrophobic quinone, and cytochrome c, a low-molecular weight hemoprotein, act as "shuttles" between the complexes. The free energy generated from the redox reactions is converted into a transmembrane proton gradient. Protons are pumped through complexes I, III, and IV of the RC, which creates a charge differential. Complex V (ATP synthase) allows protons to flow back into the mitochondrial matrix and uses the released energy to synthesize ATP. Three ATP molecules are produced for each NADH molecule oxidized.

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Section: Point Mutations In Mitochondrial Protein Synthesis Genesmentioning

confidence: 99%

Genetic Features of Mitochondrial Respiratory Chain Disorders

Rötig¹,

Münnich²

2003

Journal of the American Society of Nephrology

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“…Mitochondria are unique among cellular organelles in that they contain their own DNA (mtDNA). This is a circular double stranded molecule, 16 mtDNA also encodes 13 proteins, all of which are involved in the respiratory chain: there are seven mitochondrial subunits for complex I, one for complex 111, three for complex IV and two for complex V. All other subunits are encoded by nuclear genes, as are the membrane transporters and all matrix enzymes. Even the proteins responsible for transcription, translation and replication of mtDNA are encoded by nuclear genes (3).…”

Section: Mitochondria1 Geneticsmentioning

confidence: 99%

“…Frequent symptoms include vomiting, feeding difficulties and failure to thrive. Hypotonia is a common early sign and a number of patients have presented with recurrent episodes of apnoea (16).…”

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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“…The disease is clinically heterogeneous with phenotypes including Leigh syndrome, hepatic failure, and myopathies (12,13,15,16). COX deficiency has been associated with mitochondrial DNA mutations in COX I, II, and III (17)(18)(19)(20), with large-scale deletions of the mitochondrial genome (21) and with point mutations in mitochondrial tRNA genes (22).…”

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confidence: 99%

Cytochrome c Oxidase-deficient Patients Have Distinct Subunit Assembly Profiles

Hanson

Carrozzo

Piemonte

et al. 2001

Journal of Biological Chemistry

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Cytochrome c oxidase (COX) deficiency is the most common respiratory chain defect in childhood and is clinically heterogeneous. We report a study of six patients with COX deficiencies. Two of the patients had as yet undefined defects, three patients had Surf-1 mutations, and one patient had a 15-base pair deletion in the COX III subunit. We show that quantitative measurements of steady-state levels of subunits by monoclonal antibody reactivity, when used in combination with a discontinuous sucrose gradient methods, provide an improved diagnosis of COX deficiencies by distinguishing between kinetic, stability, and assembly defects. The two mutants of undefined etiology had a full complement of subunits with one stable and the other partially unstable to detergent solubilization. Both are likely to carry mutations in nuclear-encoded subunits of the complex. The three Surf-1 mutants and the COX III mutant each had reduced steady-state levels of subunits but variable associations of the residual subunits. This information, as well as aiding in diagnosis, helps in understanding the genotype-phenotype relationships of COX deficiencies and provides insight into the mechanism of assembly of the enzyme complex.

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Hepatic failure in disorders of oxidative phosphorylation with neonatal onset

Cited by 58 publications

References 7 publications

Genetic Features of Mitochondrial Respiratory Chain Disorders

Genetic Features of Mitochondrial Respiratory Chain Disorders

Mitochondrial respiratory chain disorders and the liver

Cytochrome c Oxidase-deficient Patients Have Distinct Subunit Assembly Profiles

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