MtDNA defects

This complex contains 11 polypeptide subunits of which only one is encoded by mtDNA. Defects of complex III are relatively uncommon and clinical presentations vary. Fatal infantile encephalomyopathies have been described in which severe neonatal lactic acidosis and hypotonia are present along with generalized amino aciduria, a Fanconi syndrome of renal insufficiency and eventual coma and death. Muscle biopsy findings may be uninformative since abnormal mitochondrial distribution is not seen, i.e., there are no ragged-red fibers. Other patients present with pure myopathy in later life and the existence of tissue-specific subunits in complex III has been suggested since one of these patients was shown to have normal complex 111 activity in lymphocytes and fibroblasts. 

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. 

This complex consists of at least 25 separate polypeptides, seven of which are encoded by mtDNA. Its catalytic action is to transfer electrons from NADH to ubiquinone, thus replenishing NAD concentrations. Complex I deficiency has been described in myopathic syndromes, characterized by exercise intolerance and lactic acidemia. In at least some patients it has been demonstrated that the defect is tissue specific and a defect in nuclear DNA is assumed. Muscle biopsy findings in these patients are typical of those in many respiratory chain abnormalities. Instead of the even distribution of mitochondria seen in normal muscle fibers, mitochondria are seen in dense clusters, especially at the fiber periphery, giving rise to the ragged-red fiber (Figure 10). This appearance is a hallmark of many mitochondrial myopathies. 

This respiratory complex consists of 13 subunits, of which the three largest are encoded on mtDNA and contain the redox centers. Complex IV is involved in a greater diversity of defects affecting human skeletal muscle than any other respiratory complex. 

The genetic classification of mitochondrial diseases divides them into three groups. Defects of mtDNA... 

All disorders except those in group 5 are due to defects of nDNA and are transmitted by Mendelian inheritance. Disorders of the respiratory chain can be due to defects of nDNA or mtDNA. Usually, mutations of nDNA cause isolated, severe defects of individual respiratory complexes, whereas mutations in mtDNA or defects of intergenomic communication cause variably severe, multiple deficiencies of respiratory chain complexes. The description that follows is based on the biochemical classification. 

Defects of complex III. Like defects of complex I, these can be due to nDNA mutations or to mtDNA mutations. The only nuclear defect described thus far does not affect a complex III subunit, but an ancillary protein needed for proper assembly, BCS1L. Mutations in BCS1L can cause a Leigh s-syndrome-like disorder or a fatal infantile disease called GRACILE (growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death). 

Lewis, W., Levine, E.S., Griniuviene, B., Tankersley, K.O., Colacino, J.M., Sommadossi, J.P., Watanabe, K.A. and Perrino, F.W. (1996) Fialuridine and its metabolites inhibit DNA polymerase gamma at sites of multiple adjacent analog incorporation, decrease mtDNA abundance, and cause mitochondrial structural defects in cultured hepatoblasts. Proceedings of the National Academy of Sciences of the United States of America, 93, 3592-3597. 

Mitochondrial diseases are caused by mutations in various mtDNA-encoded genes, most of which result in defective mitochondrial protein synthesis. 

A mutation in any of the 13 protein subunits, the 22 tRNAs, or the two rRNAs whose genes are carried in mitochondrial DNA may possibly cause disease. The 13 protein subunits are all involved in electron transport or oxidative phosphorylation. The syndromes resulting from mutations in mtDNA frequently affect oxidative phosphorylation (OXPHOS) causing what are often called "OXPHOS diseases."3-6 Mitochondrial oxidative phosphorylation also depends upon 100 proteins encoded in the nucleus. Therefore, OXPHOS diseases may result from defects in either mitochondrial or nuclear genes. The former are distinguished by the fact that they are inherited almost exclusively maternally. Most mitochondrial diseases are rare. However, mtDNA is subject to rapid mutation, and it is possible that accumulating mutants in mtDNA may be an important component of aging.h k... 

It is well established that mitochondrial function defects are not severe until the proportion of mutant mtDNA reaches a high level, which forms the basis of the concept of the threshold effect. In skeletal muscle, the level of the A3243G mutation is related to the severity of strokelike episodes, epilepsy, and dementia in patients with MELAS syndrome (C6, H14, PI). Similarly, the level of the A8344G mutation is correlated with the degree of cerebellar ataxia and myoclonus in patients with MERRF syndrome (C6). Thus, molecular genetic analysis of mtDNA mutations in muscle biopsies usually provides more definitive diagnosis of... 

Although DNA mutations in nuclear DNA may cause mitochondrial dysfunction, the majority of genetically defined mitochondrial diseases are caused by mutations in mtDNA (M15, PI, S4). Point mutations and deletions of mtDNA have been reported to be associated with or responsible for mitochondrial myopathies and/or encephalomyopathies (M15, PI, S4). Patients with such diseases usually manifest major clinical symptoms early in life and at a later stage may develop additional multisystem disorders such as encephalopathy and/or peripheral neuropathy. Most of the mitochondrial myopathies occur sporadically and are often caused by large-scale mtDNA deletions (PI). However, there are several reports on maternally inherited mitochondrial myopathy and familial mitochondrial myopathy. These patients usually harbor a specific mtDNA mutation and often exhibit defects in NADH-CoQ reductase and/or cytochrome c oxidase. 

In the past decade, a variety of mtDNA mutations have been reported to have pathogenic roles underlying a range of mitochondrial diseases (Ml5). However, aside from biochemical defects in respiration, the molecular consequences of these mtDNA mutations remain poorly understood. Recently, the consequences of several mtDNA mutations have been extensively studied at the molecular and the cellular levels. 

On the other hand, defective respiratory function elicited by the mtDNA mutation contributes to an increase in the production of ROS and free radicals, thereby causing higher oxidative stress and severe oxidative damage in affected cells (P2, W6). Because either enhanced oxidative stress or disruption of calcium homeostasis is an important factor in the triggering of cell death, mitochondrial dysfunction in tissue cells from MELAS and MERRF patients may contribute significantly to the pathogenesis of these diseases. 

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