Mitochondrial gene segregation in mammals: is the bottleneck always narrow?

Abstract

The segregation of a heteroplasmic silent polymorphism in the mitochondrial ND6 gene has been followed in a human maternal lineage comprising eight individuals and spanning three generations. Heteroplasmy persisted in all eight maternally related family members. More importantly, the frequencies of the two alleles showed relatively little variation among individuals or between generations. In contrast to the findings in other mammalian lineages, the present results indicate relatively slow mitochondrial gene segregation. A narrow bottleneck in the number of mitochondrial DNA (mtDNA) molecules, which occurs at some stage of oogenesis, has been advanced to explain rapid mammalian mitochondrial gene segregation. It is suggested here that the segregation of mitochondrial genes may be more complex than initially envisaged, and that models need to be developed that account for both rapid and slow segregation. One possibility, which reconciles both physical and genetic studies of mammalian mtDNA, is that the unit of mitochondrial segregation is the organelle itself, each containing multiple mtDNA molecules.

A mitochondrial DNA clone is associated with increased risk for Alzheimer disease.

“…Mitochondrial genomes bearing the 4336G mutation appear to be more closely related to one another than to other mitochondrial genomes present in Caucasians. This observation contrasts with the distant relatedness of mitochondrial genomes that cause early-onset mitochondrial disease such as Leber hereditary optic neuropathy (29,30), as shown in Table 2. The striking disparity in relatedness of mitochondrial genomes that cause early-and late-onset disease is most easily explained by the differential activity of negative selection to extinguish specific lineages.…”

Complementation of mutant and wild-type human mitochondrial DNAs coexisting since the mutation event and lack of complementation of DNAs introduced separately into a cell within distinct organelles.

“…There is other evidence in the literature that supports the idea that two types of mtDNA originally located in separate organelles tend to remain segregated in mammalian cells, including the gradual elimination of HeLa cell mtDNA in hybrids of HeLa cells and fibroblasts (21,49) and the complete switch, in only one or a few generations, of mtDNA genotypes in Holstein cows (2,28,36). A model assuming that the unit of segregation of mammalian mtDNA is the organelle itself and that the rapidity of segregation of mitochondrial alleles within heteroplasmic oocytes is therefore influenced by whether the individual organelles themselves are homoplasmic or heteroplasmic (23) likewise argues in favor of the genetic independence of the individual mitochondria within a mammalian cell.…”

Functional alterations of the mitochondrially encoded ND4 subunit associated with Leber's hereditary optic neuropathy

“…The specific activity of NADH:UBQ reductase (average rate of 15 nmol/min per mg protein, cf. [10]), NADH: ferricyanide and ubiquinol: cytochrome c reductase [16] were comparable in control individuals and in the members of the LHON family (cf. [6]).…”

“…Hence, less free energy is available to be converted into proton pumping and ultimately into ATP synthesis during the oxidation of NADH by the LHON-mutated complex I. The decrease in energetic efficiency of this altered complex I, although partial, may become critical with ageing and/or in relation to other aetiological factors (see [1][2][3][4][5][6][7][8][9][10] for discussion of these factors).…”

“…The functional defect that arises from the amino acid substitution (Arg34°---~His [4]) caused by this mutation is not clear yet [4,[6][7][8], even if a recent report has shown a 25% decrease in complex I activity measured with a short analogue of ubiquinone [9]. In contrast, the LHON mutation ND1/3460 has been shown to induce a strong decrease in the activity of complex I [7,9,10].…”