Mitochondrial Heteroplasmy and Disease


In addition to the nuclear genome, most eukaryotic cells also have multiple copies of a small circular genome located within the mitochondrion (mtDNA), the presence of which is critical for cellular respiration. All the mtDNA within the cells of young individuals is usually thought to be identical, a condition known as homoplasmy. An alternative situation is heteroplasmy, where there are two or more mtDNA types present within the cells of a single individual.

Keywords: mitochondrial deoxyribonucleic acid; heteroplasmy; threshold effect; cytoplast transfer; random genetic drift

Figure 1.

Relaxed replication. The mitochondrial DNA (mtDNA) of a cell turns over continuously, independent of the cell cycle; thus turnover occurs even in nondividing cells. The turnover is nonstringent – molecules may be destroyed without being replicated, in contrast to the nuclear genome. This inevitably results in some of the mtDNA lineages within the cell expanding while others become extinct. After a long enough period, all the molecules in a cell would be the progeny of a single molecule present at time zero.

Figure 2.

Threshold effect. The figure illustrates that cellular dysfunction becomes apparent only after the number of wild‐type mtDNA molecules falls below a critical level – the threshold. The number of mtDNA molecules in a cell is closely regulated in a way that is not fully understood. The diagram also illustrates the proliferation of mtDNA often seen in cells where mutated molecules have started to accumulate or, more importantly for the cell, the number of wild‐type mtDNAs has been reduced. This proliferation is believed to be random in that neither mutated nor wild‐type molecules are preferentially replicated and is thought to be an attempt to maintain the minimal required functional mtDNA content.

Figure 3.

The bottleneck. This illustration represents a situation whereby two mtDNA genotypes are present in the single‐cell embryo. The number of mtDNA molecules within a cell is effectively reduced during the bottleneck (as the embryo partitions and primordial germ cells are laid down). The copy number and intracellular variance of different genotypes are low in primordial germ cells (illustrated as slightly different shades). During maturation to primary and mature oocytes, the variance increases dramatically (oocytes, all shades) and the copy number increases. The germ‐line bottleneck results in rapid genetic drift leading to the direct loss of the mutations as individuals are formed that are homoplasmic for mutated mtDNA, swiftly exposing the new mutation to the full force of natural selection at the level of the organism. The bottleneck thus results in the loss of deleterious mutations before they accumulate within the population.



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Further Reading

Birky CW (1994) Relaxed and stringent genomes: why cytoplasmic genes don't obey Mendel's laws. Journal of Heredity 85: 355–365.

Chinnery PF, Howell N, Andrews RM and Turnbull DM (1999) Mitochondrial DNA analysis: polymorphisms and pathogenicity. Journal of Medical Genetics 36: 505–510.

Elson JL, Samuels DC, Turnbull DM and Chinnery PF (2001) Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age. American Journal of Human Genetics 68: 802–806.

Inoue K, Nakada K, Ogura A, et al. (2000) Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes. Nature Genetics 26: 176–181.

Lightowlers RN, Chinnery PF, Turnbull DM and Howell N (1997) Mammalian mitochondrial genetics: heredity, heteroplasmy and disease. Trends in Genetics 13: 450–455.

McFarland R, Clark KM, Morris AA, et al. (2002) Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation. Nature Genetics 30: 145–146.

Poulton J, Macaulay V and Marchington DR (1998) Mitochondrial genetics '98: is the bottleneck cracked? American Journal of Human Genetics 62: 752–757.

Turnbull DM and Lightowlers RN (2001) Might mammalian mitochondria merge? Nature Medicine 7: 895–896.

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How to Cite close
Elson, Joanna L, and Lightowlers, Robert N(Jan 2006) Mitochondrial Heteroplasmy and Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0006079]