Mitochondrial Genomes

The space inside the inner mitochondrial membrane is called the matrix, and it contains most of the enzymes of the TCA cycle and fatty acid oxidation. (An important exception, succinate dehydrogenase of the TCA cycle, is located in the inner membrane itself.) In addition, mitochondria contain circular DNA molecules, along with ribosomes and the enzymes required to synthesize proteins coded within the mitochondrial genome. Although some of the mitochondrial proteins are made this way, most are encoded by nuclear DNA and synthesized by cytosolic ribosomes. 

The metabolic myopathies are exceptionally complex. Mitochondrial disorders are usually multisystem disorders, in which metabolic dysfunction affects muscle, liver, CNS, and special senses (especially vision) in almost any combination. There is evidence that some forms of mitochondrial disease are inherited, and the preponderance of maternal rather than paternal inheritance is consistent with an abnormality in the mitochondrial genome because almost all (and perhaps all) mitochondria are derived from the ovum. 

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. 

In addition to the conditions described above, which involve deficiencies of individual respiratory complexes, there is another important group of mitochondrial disorders which are associated with defects of multiple respiratory complexes. The underlying abnormalities in these disorders are to be found within the mitochondrial genome, which encodes some subunits of all the respiratory complexes except complex II (Figure 12). 

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Ered Sanger, a double Nobel Prize winner, sequenced the human mitochondrial genome back in 1981. This genome codes for 13 proteins and the mitochondrion possesses the genetic machinery needed to synthesize them. Thus, the mitochondria are a secondary site for protein synthesis in eukaryotic cells. It turns out that the 13 proteins coded for by the mitochondrial genome and synthesized in the mitochondria are critically important parts of the complexes of the electron transport chain, the site of ATP synthesis. The nuclear DNA codes for the remainder of the mitochondrial proteins and these are synthesized on ribosomes, and subsequently transported to the mitochondria. 

Brain, muscle, and kidney cells, for example, all possess a few hundred or a few thousand mitochondria per cell. The human egg cell is remarkable in that it contains about 100,000 mitochondria. A sperm cell, in contrast, contains fewer than 100. New mitochondria are made as cells divide. The synthesis of new mitochondria requires that the proteins coded for by the nuclear genome and those coded for by the mitochondrial genome be mutually compatible to ensure optimal mitochondrial function. Since we can experience mutations in both nuclear and mitochondrial DNA, leading to alterations in mitochondrial proteins, long-term compatibility... 

Two mechanisms for loss of mitochondrial function have been suggested (i) damage caused by the chronic production of free radicals within the mitochondria and (ii) somatic mutations in the mitochondrial genome, which progressively accumulate during a lifetime. 

All of the complexes in the respiratory chain are made up of numerous polypeptides and contain a series of different protein bound redox coenzymes (see pp. 104, 106). These include flavins (FMN or FAD in complexes I and II), iron-sulfur clusters (in I, II, and III), and heme groups (in II, III, and IV). Of the more than 80 polypeptides in the respiratory chain, only 13 are coded by the mitochondrial genome (see p. 210). The remainder are encoded by nuclear genes, and have to be imported into the mitochondria after being synthesized in the cytoplasm (see... 

While DNA is more robust than often depicted in movies, age and extreme conditions such as a fire can substantially degrade it. In such cases, mitochondrial DNA (mtDNA) is best used. Unlike nuclear DNA, mitochondrial genome exists in thousands of copies, is less apt to degrade, and is inherited only from the mother. Here, STRs are not analyzed, but rather the focus is on variable regions of the mitochondrial genome. Such analyses take much longer but are used for situations where time is not essential. 

The answer is B. LHON often has an onset in early adulthood. It is a mitochondrial disorder usually resulting from a mutation in one of the proteins of the electron transport chain, particularly complex I, encoded by the mitochondrial genome so there is no chance that the patient can pass the disorder to his children (see Chapter 13). Cataracts would have been detected as opacity in the lenses, and glaucoma would have been identified by an elevated intraocular pressure. Macular degeneration is also associated with central vision loss but is found mainly in patients over age 65. 

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