Abstract
Several studies of tumors have revealed substantial numbers of clonally expanded somatic mutations in mitochondrial DNA (mtDNA), not observed in adjacent intact tissues. These findings were interpreted as indicating the involvement of mtDNA mutations in tumorigenesis. Such comparisons, however, ignore an important confounding factor: the monoclonal origin of tumors as opposed to the highly polyclonal nature of normal tissues. Analysis of recently published data on the incidence of somatic mutations in nontumor monoclonal cells suggests that, contrary to the prevailing view, the process of tumorigenesis may be accompanied by active selection against detrimental mtDNA mutations.
Highlights
Several different scenarios, linking mitochondrial DNA (mtDNA) mutations to tumorigenesis, can be envisioned
Cells with an elevated mtDNA mutational load may be more susceptible to carcinogenesis due to increased production of ROS by a dysfunctional electron transport chain, which may in turn promote mutagenesis of nuclear genes
It is possible that carcinogenesis is influenced to a larger extent by accumulation of mtDNA mutations in organs distal to the tissue of origin, by creating a systemically permissive environment for development of tumors
Summary
Several different scenarios, linking mtDNA mutations to tumorigenesis, can be envisioned. While the occurrence of hetero- or homoplasmic mutations to mitochondrial DNA is detectable in tumor cells, low-level heteroplasmy remains undetected by prevailing methods in essentially all normal tissues.
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