Mitochondrial respiratory chain disorder

L8. Leonard, I. V., and Schapira, A. V. H., Mitochondrial respiratory chain disorders II Neurode-generative disorders and nuclear gene defects. Lancet 355, 389-394 (2000). 

Several classes of inborn errors of metabolism in addition to inborn errors of urea synthesis can cause neonatal hyperammonemia. These include organic acidurias, fatty acid oxidation defects, amino acidopathies, and mitochondrial respiratory chain disorders. All of these disorders have a number of features in common. Labor and delivery tend to be normal, and there are no predisposing risk factors. Clinical features present after 24 h of life and are progressive. They are inherited, and thus a family history of previously affected children or neonatal deaths may be present. While most are inherited in an autosomally recessive manner, ornithine tran-scarbamoylase (OTC) deficiency is X linked, and a family history of affected males in the maternal pedigree is not uncommon. 

Leonard JV, Schapira AH. Mitochondrial respiratory chain disorders I mitochondrial DNA defects. Lancet 2000 355 299-304. 

EMA aciduria maybe associated with several other inherited and acquired conditions, including (1) glutaric acidemia type II (some cases are actually labeled to have ethylmalonic adipic aciduria),(2) disorders of the intramitochon-drial flavin adenine dinucleotide pathway, (3) mitochondrial respiratory chain disorders, and (4) ethylmalonic encephalopathy. Jamaican vomiting sickness (due to ingestion of unripe ackee fruit containing the poison hypoglycin A) and ifosfamide treatment represent two additional causes of ethylmalonic aciduria. 

Montenez JP, Van Bambeke F, Piret J, Brasseur R, Tulkens PM, Mingeot-Leclercq MP (1999) Interactions of macrolide antibiotics (erythromycin A, roxithromycin, erythromycylamine [Dmthromycin] and azithromycin) with phospholipids computer-aided conformation analysis and studies on acellular and cell culture models. Toxicol Appl Pharmacol 156 129-140 Morgan MY, Reshef R, Shah RR, Oates NS, Smith RL, Sherlock S (1984) Impaired oxidation of debrisoquine in patients with perhexiline liver injury. Gut 10 1057-1064 Morris AAM (1999) Mitochondrial respiratory chain disorders and the liver. Liver 19 357-368 Morris AAM, Taanman JW, Blake J, Cooper JM, Lake BD, Malone M, Love S, Clayton PT, Leonard JV, Schapira AHV (1998) Liver failure associated with mitochondrial DNA depletion. J Hepatol 28 556—563... 

In recent years we have increasingly encountered patients whose clinical and biochemical presentations both suggest a fatty acid oxidation disorder but who do not meet the criteria for any of the recognised P-oxidation defects. These patients may have mild to moderate reductions in fibroblast oxidation of both [9,10- Iflmyristate and [9,10- HJpalmitate, often into the VLCAD and TCHAD ranges, but show only a moderate reduction in oxidation of [9,10- H]oleate (Fig. 5). A number of such patients have presented with hepatic and/or skeletal muscle symptomatology but have subsequently proved to have a definite or probable mitochondrial respiratory chain disorder. 

Metabolic Myopathies Glycogen Storage Disease Disorders of Lipid Metabolism Respiratory Chain Disorders Mitochondrial DNA Abnormalities Myotonias, Periodic Paralyses, and Malignant Hyperpyrexia Myotonias... 

Mitochondria are unique organelles in that they contain their own DNA (mtDNA), which, in addition to ribosomal RN A (rRNA) and transfer RN A (tRNA)-coding sequences, also encodes 13 polypeptides which are components of complexes I, III, IV, and V (Anderson et al., 1981). This fact has important implications for both the genetics and the etiology of the respiratory chain disorders. Since mtDNA is maternally-inherited, a defect of a respiratory complex due to a mtDNA deletion would be expected to show a pattern of maternal transmission. However the situation is complicated by the fact that the majority of the polypeptide subunits of complexes I, III, IV, and V, and all subunits of complex II, are encoded by nuclear DNA. A defect in a nuclear-coded subunit of one of the respiratory complexes would be expected to show classic Mendelian inheritance. A further complication exists in that it is now established that some respiratory chain disorders result from defects of communication between nuclear and mitochondrial genomes (Zeviani et al., 1989). Since many mitochondrial proteins are synthesized in the cytosol and require a sophisticated system of posttranslational processing for transport and assembly, it is apparent that a diversity of genetic errors is to be expected. 

Articaine has been implicated in an episode of weakness of the limb muscles, fatigue, and anorexia in a patient with a rare respiratory chain disorder due to a genetic defect in mitochondrial DNA (Kearn-Sayre Syndrome). 

Within the past few years, there has been considerable progress in understanding the role played by the mitochondria in the cellular homeostasis of iron. Thus, erythroid cells devoid of mitochondria do not accumulate iron (7, 8), and inhibitors of the mitochondrial respiratory chain completely inhibit iron uptake (8) and heme biosynthesis (9) by reticulocytes. Furthermore, the enzyme ferrochelatase (protoheme ferro-lyase, EC 4.99.1.1) which catalyzes the insertion of Fe(II) into porphyrins, appears to be mainly a mitochondrial enzyme (10,11,12,13, 14) confined to the inner membrane (15, 16, 17). Finally, the importance of mitochondria in the intracellular metabolism of iron is also evident from the fact that in disorders with deranged heme biosynthesis, the mitochondria are heavily loaded with iron (see Mitochondrial Iron Pool, below). It would therefore be expected that mitochondria, of all mammalian cells, should be able to accumulate iron from the cytosol. From the permeability characteristics of the mitochondrial inner membrane (18) a specialized transport system analogous to that of the other multivalent cations (for review, see Ref. 19) may be expected. The relatively slow development of this field of study, however, mainly reflects the difficulties in studying the chemistry of iron. 

Respiratory-chain disorders (with mitochondrial myopathy) Lactic Various, including cytochromes b, aa, cytochrome c oxidase, NADH-coenzyme Q reductase 15.6... 

Defects of nuclear DNA also cause mitochondrial diseases. As mentioned above, the vast majority of mitochondrial proteins are encoded by nDNA, synthesized in the cytoplasm and imported into the mitochondria through a complex series of steps. Diseases can be due to mutations in genes encoding respiratory chain subunits, ancillary proteins controlling the proper assembly of the respiratory chain complexes, proteins controlling the importation machinery, or proteins controlling the lipid composition of the inner membrane. All these disorders will be transmitted by mendelian inheritance. From a biochemical point of view, all areas of mitochondrial metabolism can be affected (see below). 

A slowly progressive congenital neuromuscular disorder was reported in which the respiratory chain-linked energy transfer at a level common to all three energy coupling sites of respiratory chain was defective.52 Uncouplers of mitochondrial oxidative phosphorylation (2,4-dinitrophenol and carbonylcyanide-m-chlorophenylhydrazone) (5) produced mitochondrial myopathy in rats.53... 

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