Possibility of selection against mtDNA mutations in tumors (original) (raw)
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Mitochondrial DNA (mtDNA) and Cancer Pathogenesis – The Role of mtDNA Mutations: A Review
Global Journal of Cancer Case Reports
Mitochondria are essential metabolic organelles as produce cellular energy by oxidative phosphorylation (OXPHOS), produce reactive oxygen species (ROS) as a by-product, and regulate functions such as apoptosis via the mitochondrial permeability transition pore (mtPTP). However, mitochondria are also responsible for multiple cellular functions such as, cellular development, growth, signals interaction from mitochondria to nucleus and nucleus to mitochondria, and are involved in miscellaneous metabolic pathways. Those processes are accomplished by several protein complexes and mitochondrial respiratory chains (MRC) encoded by nuclear and mitochondrial DNA (mtDNA), as are assembled from both nuclear DNA (nDNA) and mitochondrial DNA genes. The mt DNA is a circular, double-stranded molecule 16,569 base pairs (bp) in length, contains 37 genes which code 13 polypeptides, 2 genes of rRNA (12S,16S), and 22 genes of tRNA, and is present in thousands of copies in each human cell. Almost 90 years ago, Otto Warburg hypothesized that a defect in energy metabolism is the initial cause of cancer. Mitochondria have also active roles in a diversity of other processes, including inflammation, whereas their functions seem to influence some of cancer hallmarks, which include evasion of cell death, genome instability, tumor-promoting inflammation and metastasis. Defects in mitochondrial function which are associated with bioenergetic deficiencies can lead to nDNA genome instability, resistance to apoptosis and induction of NADPH oxidase which is implicated in ROS production. Researches have demonstrated that mtDNA shows a high mutations rate most of which are responsible for mild mitochondrial dysfunction and its essential role in tumorigenesis, whereas enhanced mitochondrial biogenesis is frequently recorded in cancer cells. Although mtDNA has been implicated in cancer pathogenesis, its role remains to be defined. The aim of the current article was to examine the role of mtDNA mutations in cancer pathogenesis.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2012
There have been many reports of mitochondrial DNA (mtDNA) mutations associated with human malignancies. We have observed allelic instability in UV-induced cutaneous tumors at the mt-Tr locus encoding the mitochondrial tRNA for arginine. We examined the effects of somatic alterations at this locus by modeling the change in a uniform nuclear background by generating cybrids harboring allelic variation at mt-Tr. We utilized the naturally occurring mtDNA variation at mt-Tr within the BALB/cJ (BALB) and C57BL/6J (B6) strains of Mus musculus to transfer their mitochondria into a mouse ρ 0 cell line that lacked its own mtDNA. The BALB haplotype containing the mt-Tr 9821insA allele produced significant changes in cellular respiration (resulting in lowered ATP production), but increased rates of cellular proliferation in cybrid cells. Furthermore, the mtDNA genotype associated with UV-induced tumors endowed the cybrid cells with a phenotype of resistance to UV-induced apoptosis and enhanced migration and invasion capabilities. These studies support a role for mtDNA changes in cancer.
Nat Genet, 2001
Researchers in several laboratories have reported a high frequency of homoplasmic mitochondrial DNA (mtDNA) mutations in human tumors. This observation has been interpreted to reflect a replicative advantage for mutated mtDNA copies, a growth advantage for a cell containing certain mtDNA mutations, and/or tumorigenic properties of mtDNA mutations. We consider another possibility-that the observed homoplasmy arose entirely by chance in tumor progenitor cells, without any physiological advantage or tumorigenic requirement. Through extensive computer modeling, we demonstrate that there is sufficient opportunity for a tumor progenitor cell to achieve homoplasmy through unbiased mtDNA replication and sorting during cell division. To test our model in vivo, we analyzed mtDNA homoplasmy in healthy human epithelial tissues and discovered that the model correctly predicts the considerable observed frequency of homoplasmic cells. Based on the available data on mitochondrial mutant fractions and cell division kinetics, we show that the predicted frequency of homoplasmy in tumor progenitor cells in the absence of selection is similar to the reported frequency of homoplasmic mutations in tumors. Although a role for other mechanisms is not excluded, random processes are sufficient to explain the incidence of homoplasmic mtDNA mutations in human tumors.
Clonal expansion of different mtDNA variants without selective advantage in solid tumors
Mutation research, 2009
In search of tumor-specific mitochondrial DNA (mtDNA) mutations in head and neck squamous cell cancer, we found heteroplasmy in the blood of two individuals, i.e., these individuals carried two alleles of mtDNA. In both cases, the tumor was found to be homoplasmic, i.e., it contained only one of the two mtDNA alleles present in blood. More interestingly, in one case the tumor had acquired the wild-type allele, while in the other case it contained the mutant allele only. Sequencing of the whole 16.5 kb mtDNA showed that the observed heteroplasmic positions in the D-loop region, nucleotides 152 and 16187, respectively, were the only differences between tumor and blood mtDNA genotypes in these individuals. Our findings thus strongly support the hypothesis that accumulation of mtDNA mutations in solid tumors occurs by clonal and random expansion of pre-existing alleles and is not necessary for the metabolic changes generally associated with tumor formation, the Warburg effect.
Enhanced tumorigenicity by mitochondrial DNA mild mutations
Oncotarget, 2015
To understand how mitochondria are involved in malignant transformation we have generated a collection of transmitochondrial cybrid cell lines on the same nuclear background (143B) but with mutant mitochondrial DNA (mtDNA) variants with different degrees of pathogenicity. These include the severe mutation in the tRNALys gene, m.8363G>A, and the three milder yet prevalent Leber's hereditary optic neuropathy (LHON) mutations in the MT-ND1 (m.3460G>A), MT-ND4 (m.11778G>A) and MT-ND6 (m.14484T>C) mitochondrial genes. We found that 143B ρ0 cells devoid of mtDNA and cybrids harboring wild type mtDNA or that causing severe mitochondrial dysfunction do not produce tumors when injected in nude mice. By contrast cybrids containing mild mutant mtDNAs exhibit different tumorigenic capacities, depending on OXPHOS dysfunction.The differences in tumorigenicity correlate with an enhanced resistance to apoptosis and high levels of NOX expression. However, the final capacity of the di...
Mitochondrial DNA mutations in human cancer
Oncogene, 2006
Somatic mitochondrial DNA (mtDNA) mutations have been increasingly observed in primary human cancers. As each cell contains many mitochondria with multiple copies of mtDNA, it is possible that wild-type and mutant mtDNA can co-exist in a state called heteroplasmy. During cell division, mitochondria are randomly distributed to daughter cells. Over time, the proportion of the mutant mtDNA within the cell can vary and may drift toward predominantly mutant or wild type to achieve homoplasmy. Thus, the biological impact of a given mutation may vary, depending on the proportion of mutant mtDNAs carried by the cell. This effect contributes to the various phenotypes observed among family members carrying the same pathogenic mtDNA mutation. Most mutations occur in the coding sequences but few result in substantial amino acid changes raising questions as to their biological consequence. Studies reveal that mtDNA play a crucial role in the development of cancer but further work is required to establish the functional significance of specific mitochondrial mutations in cancer and disease progression. The origin of somatic mtDNA mutations in human cancer and their potential diagnostic and therapeutic implications in cancer are discussed. This review article provides a detailed summary of mtDNA mutations that have been reported in various types of cancer. Furthermore, this review offers some perspective as to the origin of these of mutations, their functional consequences in cancer development, and possible therapeutic implications.
Polymorphic mutations in mouse mitochondrial DNA regulate a tumor phenotype
Mitochondrion, 2013
To examine whether polymorphic mtDNA mutations that do not induce significant respiration defects regulate phenotypes of tumor cells, we used mouse transmitochondrial tumor cells (cybrids) with nuclear DNA from C57BL/6 (B6) strain and mtDNA from allogenic C3H strain. The results showed that polymorphic mutations of C3H mtDNA in the cybrids induced hypoxia sensitivity, resulting in a delay of tumor formation on their subcutaneous inoculation into B6 mice. Therefore, the effects of polymorphic mutations in normal mtDNA have to be carefully considered, particularly when we apply the gene therapy to the embryos to replace their pathogenic mtDNA by normal mtDNA.
Generation, function, and prognostic utility of somatic mitochondrial DNA mutations in cancer
Environmental and Molecular Mutagenesis, 2000
Exciting new studies are increasingly strengthening the link between mitochondrial mutagenesis and tumor progression. Here we provide a comprehensive review and meta-analysis of studies reporting on mitochondrial DNA mutations in common human cancers. We discuss possible mechanisms by which mitochondrial DNA mutations may influence carcinogenesis, outline important caveats for interpreting the detected mutations-particularly differentiating causality from association-and suggest how new mutational assays may help resolve fundamental controversies in the field and delineate the origin and expansion of neoplastic cell lineages. Finally, we discuss the potential clinical utility of mtDNA mutations for improving the sensitivity of early cancer diagnosis, rapidly detecting cancer recurrence, and predicting the disease outcome. Environ.