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Mitochondrial DNA variation and cancer


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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Fig. 1: Mitochondrial DNA variants can play inductive and adaptive roles in oncogenesis.
Fig. 2: Mitochondrial biology and metabolism and its relationship to the epigenome.
Fig. 3: Human mtDNA map showing representative variants.
Fig. 4: Examples of cancer-relevant classes of mtDNA variants.


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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.

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P.K.K. and D.C.W. contributed to all aspects of the article. L.N.S., S.Z. and M.T.L. researched the literature and contributed to the discussion of content and reviewing or editing of the article.

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Correspondence to Douglas C. Wallace.

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D.C.W. has associations with Pano Therapeutics and Medical Excellence Capital. The other authors declare no competing interests.

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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).

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