Understanding Mitochondrial Polymorphisms in Cancer

Abstract

Alterations in mitochondrial DNA (mtDNA) were once thought to be predominantly innocuous to cell growth. Recent evidence suggests that mtDNA undergo naturally occurring alterations, including mutations and polymorphisms, which profoundly affect the cells in which they appear and contribute to a variety of diseases, including cardiovascular disease, diabetes, and cancer. Furthermore, interplay between mtDNA and nuclear DNA has been found in cancer cells, necessitating consideration of these complex interactions for future studies of cancer mutations and polymorphisms. In this issue of Cancer Research, Vivian and colleagues utilize a unique mouse model, called Mitochondrial Nuclear eXchange mice, that contain the nuclear DNA from one inbred mouse strain, and the mtDNA from a different inbred mouse strain to examine the genomewide nuclear DNA methylation and gene expression patterns of brain tissue. Results demonstrated there were alterations in nuclear DNA expression and DNA methylation driven by mtDNA. These alterations may impact disease pathogenesis. In light of these results, in this review, we highlight alterations in mtDNA, with a specific focus on polymorphisms associated with cancer susceptibility and/or prognosis, mtDNA as cancer biomarkers, and considerations for investigating the role of mtDNA in cancer progression for future studies.

Roles of the mitochondrial genetics in cancer metastasis: not to be ignored any longer

“…Therefore, review of mtDNA haplogroup association below is not complete, but rather provides examples of compelling mtDNA polymorphism correlations with cancer susceptibility. For a more thorough analysis of the strengths and weaknesses of animal models studying mtDNA polymorphisms in cancer risk association, please refer to a recent review from Bussard and Siracusa [97]. Following a brief discussion of the population-based studies, we will briefly summarize some of the newer experimental approaches to dissect the contributions of mitochondrial DNA in cancer progression and metastasis.…”

Genomic heterogeneity meets cellular energetics: crosstalk between the mitochondria and the cell cycle

“…However, the role of mtDNA mutations or copy number variations as potential causative agents in cancer development have not been fully established due to the technological difficulties of manipulating the mtDNA genome. Studies in mice that have mtDNA from one strain and nuclear DNA from another strain (i.e., mice generated by mitochondrial-nuclear exchange) show effects in cancer progression models including changes in tumor size and metastatic burden [49] , suggesting that the mtDNA can affect cancer progression.…”

Mitochondrial polymorphisms contribute to aging phenotypes in MNX mouse models

“…For example, C3H/HeN mice do not contain a mutation in the toll-like receptor 4 (TLR4); whereas, C3H/HeJ mice do. Such differences are also manifest during the generation of conplastic strains, which allows comparison between strains with similar or identical nuclear genomes but differing in their mitochondrial genome, thus providing evidence that the mitochondrial genome influences phenotypes [52,53]. …”

“…Although several strategies have been used to assess the contributions of mtDNA to disease, strengths and limitations exist for each (reviewed in [53,36]). In order to avoid use of mutagens, off-target effects of drugs and nDNA crossover complications to studying mitochondrial genetic contributions, we developed Mitochondrial-Nuclear Exchange (MNX) mice [37,59,39,15].…”