Variation in the mitochondrial DNA (mtDNA) sequence is common in certain tumours. Two classes of cancer mtDNA variants can be identified: de novo mutations that act as ‘inducers’ of carcinogenesis and functional variants that act as ‘adaptors’, permitting cancer cells to thrive in different environments. These mtDNA variants have three origins: inherited variants, which run in families, somatic mutations arising within each cell or individual, and variants that are also associated with ancient mtDNA lineages (haplogroups) and are thought to permit adaptation to changing tissue or geographic environments. In addition to mtDNA sequence variation, mtDNA copy number and perhaps transfer of mtDNA sequences into the nucleus can contribute to certain cancers. Strong functional relevance of mtDNA variation has been demonstrated in oncocytoma and prostate cancer, while mtDNA variation has been reported in multiple other cancer types. Alterations in nuclear DNA-encoded mitochondrial genes have confirmed the importance of mitochondrial metabolism in cancer, affecting mitochondrial reactive oxygen species production, redox state and mitochondrial intermediates that act as substrates for chromatin-modifying enzymes. Hence, subtle changes in the mitochondrial genotype can have profound effects on the nucleus, as well as carcinogenesis and cancer progression.
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This work was supported by a Howard Hughes Medical Institute Research Fellowship awarded to P.K.K., and US National Institutes of Health grants NS021328, MH108592 and OD010944, and US Department of Defense grants W81XWH-16-1-0401v and W81XWH-21-1-0128 awarded to D.C.W.
D.C.W. has associations with Pano Therapeutics and Medical Excellence Capital. The other authors declare no competing interests.
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The simultaneous presence of two or more mitochondrial DNA genotypes in one cell.
- Myoclonic epilepsy and ragged red fibre (MERRF) syndrome
A progressive disease including seizures, muscle spasm and weakness, lack of muscle control, abnormal sensations in limbs and fat growth (lipomas).
- Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome
A heterogenous phenotype characterized by epilepsy or dementia, with characteristic elevated lactate levels in blood and cerebrospinal fluid, as well as episodes of selective loss of vision, sensation and speech.
- Leigh syndrome
Also known as subacute necrotizing encephalopathy, a disease of typically infantile onset with psychomotor retardation, floppiness, brainstem dysfunction and abnormal body movements.
The presence of only one mitochondrial DNA genotype within one cell.
- Leber hereditary optic neuropathy
A disease of early adulthood with rapidly progressive central loss of vision sequentially in both eyes.
- Pearson syndrome
A disease of the newborn caused by mitochondrial DNA deletion presenting with anaemia, vomiting and failure to thrive.
- Kearns–Sayre syndrome
A disease with typical onset before the age of 20 years with abnormal pigmentation of the retina and progressive abnormal eye movements, as well as cardiac conduction abnormalities and cerebellar dysfunction.
- Chronic progressive external ophthalmoplegia
Slowly progressive weakness of extraocular eye muscles resulting in abnormal eye movements and lid lag.
The transfer of mitochondrial DNA sequences into the nucleus.
- Transmitochondrial cybrid
A cell line in which the mitochondrial and mitochondrial DNA encompassed within an enucleated cytoplasmic fragment is fused to a recipient cell, resulting in a cytoplasmic hybrid (cybrid) with the nucleus of the recipient cell but the mitochondrial and mitochondrial DNA of the donor cell.
Benign tumours harbouring a large numbers of cytoplasmic mitochondria.
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Kopinski, P.K., Singh, L.N., Zhang, S. et al. Mitochondrial DNA variation and cancer. Nat Rev Cancer 21, 431–445 (2021). https://doi.org/10.1038/s41568-021-00358-w