Each somatic cell has hundreds to several thousand mitochon dria, and each mitochondrion contains two to ten copies of mtDNA. mtDNA consists of a single double-stranded circular molecule, and its 16 569 nucleotide-long genome encodes 24 structural RNAs (22 tRNAs and 2 rRNAs), which are required for mitochondrial protein synthesis; in addition it encodes 13 protein subunits belonging to four enzyme complexes, all involved, directly or indirectly, in the generation of adenosine triphosphate (ATP) through oxidative phosphorylation (Figure 12.3). Replication, transcription and translation of mtDNA are all quite distinct from their nuclear DNA equivalents.
Since mitochondria are abundant in the cytoplasm of the mature oocyte but absent from that part of the sperm cell that enters it at the time of fertilization, the hereditary transmission of mtDNA is exclusively through the maternal germline. Consequently, a mitochondrial disease can be transmitted from a mother to all of her children, whether male or female — a non-Mendelian form of inheritance.
mtDNA is estimated to be at least 10 times more vulnerable than nuclear DNA to mutations and their consequences for various reasons. Firstly, it is constantly exposed to oxygen free radicals generated by oxidative phosphorylation; secondly, mitochondria largely lack effective DNA repair mechanisms; thirdly, because most of the mtDNA sequence is coding, many more mutations will be reflected in the structure of its protein products. On the other hand, since there are so many copies of mtDNA in each cell, mutant mtDNA may coexist with normal mtDNA, a situation called 'heteroplasmy' (the opposite of ho-moplasmy). The phenotype of a particular cell or organ will depend on the relative proportions of normal and mutated mtDNA. Since, unlike nuclear chromosomes, mtDNA molecules have no rigorous mechanism for segregation at either mitosis or meiosis, the inheritance of mtDNA mutations is rather unpredictable; and since heteroplasmy may exist even in oocytes, this further complicates the non-Mendelian inheritance of diseases caused by mtDNA mutations.
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