MtDNA mitochondrial

LCHAD long chain 3-hydroxyacyl-CoA dehydrogenase mtDNA mitochondrial DNA... 

Fig. 3.8.1 The genetic complexity of the mitochondrial respiratory chain biogenesis. CI-V Respiratory chain complexes I-V, mtDNA mitochondrial DNA...

Figure 7.47 The mechanism of cardiotoxicity of doxorubicin. The drug can acquire electrons from mitochondrial complex I. The quinone thus produced can donate the electron to oxygen, and the superoxide produced damages heart tissues and mtDNA. Abbreviation mtDNA, mitochondrial DNA.

Structure of a mitochondrion showing schematic representation of the electron transport chain and ATP synthesizing structures on the inner membrane. mtDNA = mitochondrial DNA mtRNA = mitochondrial RNA. 

Mitochondria have their own DNA (mtDNA) and genetic continuity. This DNA only encodes 13 peptide subunits synthesized in the matrix that are components of complexes I, III, IV, and V of the respiratory chain. Most mitochondrial proteins are synthesized on cytoplasmic ribosomes and imported by specific mechanisms to their specific locations in the mitochondrion (see below). 

Mitochondria are unique organelles in man and higher animals in that they contain their own genome. Mitochondrial DNA (mtDNA) in humans is a small (16.5 kb), circular genome that encodes only 13 proteins, 22 transfer RNA (tRNA), and 2 ribosomal RNA (rRNA) molecules. mtDNA is inherited only from the mother and is present in multiple copies within one mitochondrion. 

Mitochondrial DNA is transcribed as a polycistronic RNA which is subsequently cleaved to generate the various mature mRNA, tRNA, and rRNA (Clayton, 1984). The 13 proteins encoded by mtDNA are all components of the respiratory chain and are seven subunits of complex I, one subunit of complex III, three subunits of complex IV, and two subunits of complex V. 

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 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. 

The majority of the peptides in mitochondria (about 54 out of 67) are coded by nuclear genes. The rest are coded by genes found in mitochondrial (mt) DNA. Human mitochondria contain two to ten copies of a smaU circular double-stranded DNA molecule that makes up approximately 1% of total ceUular DNA. This mtDNA codes for mt ribosomal and transfer RNAs and for 13 proteins that play key roles in the respiratory chain. The linearized strucmral map of the human mitochondrial genes is shown in Figure 36-8. Some of the feamres of mtDNA are shown in Table... 

An important feamre of human mitochondrial mtDNA is that—because aU mitochondria are contributed by the ovum during zygote formation—it is transmitted by maternal nonmendefian inheritance. 

The third human DNA SRM developed by NIST was designed to meet the need for quality control when amplifying and sequencing human mitochondrial DNA (mtDNA). 

Mitochondrial DNA is inherited maternally. What makes mitochondrial diseases particularly interesting from a genetic point of view is that the mitochondrion has its own DNA (mtDNA) and its own transcription and translation processes. The mtDNA encodes only 13 polypeptides nuclear DNA (nDNA) controls the synthesis of 90-95% of all mitochondrial proteins. All known mito-chondrially encoded polypeptides are located in the inner mitochondrial membrane as subunits of the respiratory chain complexes (Fig. 42-3), including seven subunits of complex I the apoprotein of cytochrome b the three larger subunits of cytochrome c oxidase, also termed complex IV and two subunits of ATPase, also termed complex V. 

TABLE 42-1 Clinical features of mitochondrial diseases associated with mtDNA mutations... 

Because there are hundreds or thousands of copies of mtDNA in each cell, the phenotypic expression of a mitochondrially encoded gene depends on the relative proportions of mutant and wild-type mtDNAs within a cell this is termed the threshold effect . 

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

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. 

DNA, or deoxyribonucleic acid, is the hereditary material in humans and almost all other organisms. Nearly every cell in a person s body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA). 

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