Mitochondrial DNA and Diseases


The mitochondrial genome (mtDNA, mitochondrial deoxyribonucleic acid) is an essential source of extranuclear DNA in mammalian cells, located in the matrix of the organelle. It is much smaller than chromosomal DNA (only 16 569 bp) but thousands of copies per nucleated cell are found in nucleoprotein complexes termed nucleoids, which may constitute the heritable unit. mtDNA is maternally inherited and encodes 13 polypeptides, all fundamental for coupling cellular respiration to ATP (adenosine triphosphate) production. Consequently, mutated mtDNA can cause profound cellular dysfunction and death. Many pathogenic mtDNA mutations are known: single point mutations and rearrangements underlie clinical disorders known as mitochondrial cytopathies or encephalomyopathies; several nuclear gene mutations are known to cause mtDNA rearrangements; there exists an association between mtDNA deletions and the ageing process. Models explain how deletions may occur, but it is unknown how these deleted molecules predominate in individual cells over time, a process termed clonal expansion.

Keywords: mitochondrial DNA; mitochondrial disease; heteroplasmy; homoplasmy

Figure 1.

Schematic representation of the human mitochondrial genome. The human mitochondrial genome is a circular, closed, covalent molecule of 16 569 bp. The two strands are represented here, the inner being the light (L) strand and the outer the heavy (H) strand. The positions of the ribosomal ribonucleic acids (rRNAs), protein coding regions and the punctuating transfer RNAs (tRNAs), shown as small blue circles, are indicated on the appropriate strands. Both of the two heavy and one light strand promoters (HSP1/2 and LSP) are located within the noncoding region. There is substantial current debate about the exact origins of mtDNA replication.

Figure 2.

Schematic of the mitochondrial respiratory chain components. The process of oxidative phosphorylation couples electron transfer and proton pumping. The five complexes involved are represented in this diagram, together with the electron carriers ubiquinol (Q) and cytochrome c (C). Complexes I, III, IV and V comprise polypeptides encoded by both the nuclear and the mitochondrial genome. In total, the human mitochondrial genome encodes 13 polypeptides, all of which are members of the respiratory chain: 7 of complex I, 1 of complex III, 3 of complex IV and 2 of complex V. FAD, flavin–adenine dinucleotide; NAD, nicotinamide–adenine dinucleotide; ADP, adenosine diphosphate; Pi, inorganic phosphate and ATP, adenosine triphosphate.



Anderson S, Bankier AT, Barrell BG et al. (1981) Sequence and organisation of the human mitochondrial genome. Nature 290: 457–465.

Bender A, Krishnan KJ, Morris CM et al. (2006) High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nature Genetics 38: 515–517.

Blok RB, Gook DA, Thorburn DR and Dahl HHM (1997) Skewed segregation of the mtDNA nt8993 (T → G) mutation in human oocytes. American Journal of Human Genetics 60: 1495–1501.

Cerritelli SM, Frolova EG, Feng C et al. (2003) Failure to produce mitochondrial DNA results in embryonic lethality in RNase h1 null mice. Molecular Cell 11: 807–815.

Chinnery PF, Howell N, Lightowlers RN and Turnbull DM (1997) Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes. Brain 120: 1713–1721.

Cortopassi GA and Arnheim N (1990) Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Research 18(23): 6927–6933.

Dunbar DR, Moonie PA, Jacobs HT and Holt IJ (1995) Different cellular backgrounds confer a marked advantage to either mutant or wild‐type mitochondrial genomes. Proceedings of the National Academy of Sciences of the USA 92: 6562–6566.

Enriquez JA, Chomyn A and Attardi G (1995) MtDNA mutation in MERRF syndrome causes defective aminoacylation of tRNALys and premature translation termination. Nature Genetics 10: 47–55.

Falkenberg M, Gaspari M, Rantanen A et al. (2002) Mitochondrial transcription factors B1 and B2 activate transcription of human mtDNA. Nature Genetics 31: 289–294.

Goto Y‐I, Nonaka I and Horai S (1990) A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348: 651–653.

Grossman LI, Watson R and Vinograd J (1973) The presence of ribonucleotides in mature closed‐circular mitochondrial DNA. Proceedings of the National Academy of Sciences of the USA 70: 3339–3343.

Holt IJ, Harding AE and Morgan‐Hughes JA (1988) Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331: 717–719.

Holt IJ, Lorimer HE and Jacobs HT (2000) Coupled leading‐ and lagging‐strand synthesis of mammalian mitochondrial DNA. Cell 100: 515–524.

Krishnan KJ, Reeve AK, Samuels DC et al. (2008) What causes mtDNA deletions in human cells? Nature Genetics 40(3): 275–279.

Martin M, Cho J, Cesare AJ, Griffith JD and Attardi G (2005) Termination factor‐mediated DNA loop between termination and initiation sites drives mitochondrial rRNA synthesis. Cell 123: 1227–1240.

Park CB, Asin‐Cayuela J, Cámara Y et al. (2007) MTERF3 is a negative regulator of mammalian mtDNA transcription. Cell 130(2): 211–213.

Poulton J, Deadman ME and Gardiner RM (1989) Duplications of mitochondrial DNA in mitochondrial myopathy. Lancet 1: 236–240.

Scorrano L (2007) Multiple functions of mitochondria‐shaping proteins. Novartis Foundation Symposium 287: 47–55, discussion 55–59.

Shoffner JM, Lott MT, Lezza AMS et al. (1990) Myoclonic epilepsy and ragged‐red fibre disease (MERRF) is associated with a mitochondrial DNA tRNALys mutation. Cell 61: 931–937.

Trifunovic A, Wredenberg A, Falkenberg M et al. (2004) Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429: 417–423.

Wallace DC, Singh G, Lott MT et al. (1988) Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242: 1427–1430.

Yasukawa T, Reyes A, Cluett TJ et al. (2006) Replication of vertebrate mitochondrial DNA entails transient ribonucleotide incorporation throughout the lagging strand. EMBO Journal 25: 5358–5371.

Further Reading

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

Falkenberg M, Larsson N‐G and Gustafsson CM (2007) DNA replication and transcription in mammalian mitochondria. Annual Review of Biochemistry 76: 679–699.

Howell N (1999) Human mitochondrial diseases: answering questions and questioning answers. International Review of Cytology 186: 49–116.

Shoubridge EA and Wai T (2008) Sidestepping mutational meltdown. Science 319: 914–915.

Taylor RW and Turnbull DM (2005) Mitochondrial DNA mutations in human disease. Nature Reviews Genetics 6(5): 389–402.

Zeviani M and Carelli V (2007) Mitochondrial disorders. Current Opinion in Neurology 20: 564–571.

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Boesch, Pierre, Lightowlers, Robert N, and Chrzanowska‐Lightowlers, Zofia MA(Dec 2008) Mitochondrial DNA and Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001462.pub2]