ReviewMitochondrial DNA in human malignancy
Introduction
Mammalian cells possess two different and interdependent genomes, which comprise a dual genetic system. The diploid (2N) nucleus of a human cell contains approximately 6 billion base pairs, whereas mitochondria contain a 16,569 base pair genome in 100–1000 copies per cell [1], [2]. The mitochondrial genome is more vulnerable to oxidative damage and undergoes a higher rate of mutation than does the nuclear genome [3], [4]. Tumor formation is often associated with mitochondrial DNA (mtDNA) mutations and alterations in mitochondrial genomic function. Mitochondrial aberrations have been identified in cancer of the bladder, breast, colon, head and neck, kidney, liver, lung, stomach and in the hematologic malignancies, leukemia and lymphoma [5], [6], [7], [8], [9], [10], [11], [12]. Altered expression and mutations in mtDNA-encoded Complexes I, III–V, as well as mutations in the hypervariable regions of mtDNA comprise some of the mitochondrial genomic aberrations found in cancer tissue. The majority of proteins in mitochondria are encoded by the nuclear genome, and intergenomic communication is necessary for mitochondrial synthesis and function. Findings of mtDNA mutations in tumor cells are consistent with reports that tumor cells are subjected to constitutive oxidative stress [13]. Moreover, reactive oxygen species (ROS) function in both initiation and promotion of carcinogenesis [14]. Further studies of mtDNA aberrations in tumors combined with studies of intergenomic signal communication pathways will assist in clarifying the role of mtDNA in the commonly occurring solid tumors and hematologic malignancies.
Section snippets
Characteristics of mitochondrial DNA
Mitochondria are semi-autonomously functioning organelles, which contain a resident genome, and replicate, translate and transcribe their own DNA [15], [16]. Mitochondria are responsible for generating approximately 90% of cellular adenosine triphosphate (ATP) through the process of oxidative phosphorylation [17]. mtDNA comprise 0.1–1.0% of the total DNA in most mammalian cells [18]. Each organelle contains 2–10 copies of mtDNA molecules, and each human cell contains more than 1000 copies of
Mitochondrial DNA aberrations in solid tumors and hematologic malignancies
Alterations in the multimeric membrane protein complexes which comprise the mitochondrial oxidative phosphorylation system have been reported in solid tumors and in hematologic malignancies. Included among the solid tumors are cancers of the bladder, breast, colon, stomach, liver, kidney, lung and head and neck. Hematolgic malignancies include acute and chronic leukemias, myelodysplastic syndrome and lymphoma.
Acute and chronic leukemia, MDS
Clayton and Vinograd utilized electron microscopy and identified changes in the structure of mtDNA obtained from leukocytes of three leukemic patients [11]. Circular dimers, catenated dimers and catenated trimers representing novel structures of mtDNA were found. Circular dimers are composed of closed, circular duplex molecules of mtDNA, whereas the catenated structures consist of interlocking pairs of mtDNA. Circular dimers and catenated structures are thought to have a role in the etiology of
Discussion
The extent to which cancer is caused by or is a consequence of mitochondrial genomic alterations is unknown, but substantial data suggest an involvement in the carcinogenic process. Mitochondria have long been suspected as contributors to carcinogenesis [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66]. Earlier models described how, during cell division, random distribution of mitochondria containing accumulated lesions in just a small number of cells might lead to cancer [66],
Acknowledgements
The authors are grateful to Drs. Jack A. Taylor and Bennett Van Houten for their critical review of the manuscript.
References (134)
- et al.
Mitochondrial mutagenesis in human cells and tissues
Mutat. Res.
(1999) The mitochondrial genome: transcription, translation and replication
Biochim. Biophys. Acta
(1999)- et al.
Mitochondrial DNA damage by anticancer agents
Pharmac. Ther.
(1992) Mitochondrial DNA alterations as ageing-associated molecular events
Mutat. Res.
(1992)- et al.
Revolution in mitochondrial medicine
FEBS Lett.
(1999) Human Complex I deficiency: clinical spectrum and involvement of oxygen free radicals in the pathogenicity of the defect
Biochim. Biophys. Acta
(1998)Replication of animal mitochondrial DNA
Cell
(1982)- et al.
Increased level of mitochondrial gene expression in polyps of familial polyposis coli patients. Biochem. Biophys. Res. Commun.
(1989) - et al.
Mitochondria in oncogenesis
Lancet
(1975) - et al.
Are mitochondrial DNA mutations involved in the carcinogenic process?
Mutat. Res.
(1987)
Do mitochondrial DNA fragments promote cancer and aging?
FEBS Lett.
Mitochondrial mutations may increase oxidative stress: implications for carcinogenesis and aging?
Free Rad. Biol. Med.
Role of mitochondria in carcinogenesis
Eur. J. Cancer
New evidence for the insertion of mitochondrial DNA into the human genome: significance for cancer and aging
Mutat. Res.
Might cancer be a failed response to renegade mitochondria?
J. Theoretical Biol.
Preferential mitochondrial DNA injury caused by glucose oxidase as a steady generator of hydrogen peroxide in human fibroblasts
Mutat. Res.
The rate of mitochondrial mutagenesis is faster in mice than in humans
Mutat. Res.
Mitochondrial damage induced by conditions of oxidative stress
Free Rad. Biol. Med.
Repair of DNA damage in mitochondria
Mutat. Res.
Repair of oxidative damage within the mitochondrial DNA of RINr 38 cells
J. Biol. Chem.
Repair of oxidative damage to nuclear and mitochondrial DNA in mammalian cells
J. Biol. Chem.
Mitochondrial DNA repair pathways
Mutat. Res.
Oxidative DNA damage processing in nuclear and mitochondrial DNA
Biochimie
Exonucleolytic proof reading enhances the fidelity of DNA synthesis by chick embryo DNA polymerase-gamma
J. Biol. Chem.
Mechanism of somatic mitochondrial DNA mutations associated with age and diseases
Biochim. Biophys. Acta
Superoxide and hydrogen peroxide in relation to mammalian cell proliferation
Free Rad. Biol. Medicine
Oxidative damage to mitochondrial DNA and its relationship to aging
Int. J. Biochem. Cell Biol.
The beneficial effects of dietary restriction: reduced oxidative damage and enhanced apoptosis
Mutat. Res.
Cell culture models for oxidative stress: superoxide and hydrogen peroxide versus normobaric hyperoxia
Mutat. Res.
Molecular genetic aspects of human mitochondrial disorders
Annu. Rev. Genetics
Mitochondrial DNA and disease
Lancet
Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress
Proc. Natl. Acad. Sci. U.S.A.
Mitochondrial DNA mutations in normal and tumor tissues from breast cancer patients
Cytogenet. Cell Genet.
Increased steady-state levels of several mitochondrial and nuclear gene transcripts in rat hepatoma with a low content of mitochondria
Eur. J. Biochem.
Circular dimer and catenate forms of mitochondrial DNA in human leukaemic leucocytes
Nature
Oxidative stress and mitochondrial DNA mutations in human aging
Proc. Soc. Exp. Biol. Med.
Mitochondrial DNA in aging and disease
Scientific Am.
The mitochondrion that time forgot
Nature
Diseases of the mitochondrial DNA
Annu. Rev. Biochem.
Mitochondrial mutations and human disease
Environ. Mol. Mutagen.
Mitochondrial genetics and human disease
BioEssays
Cited by (403)
Inhibition of mitochondrial superoxide promotes the development of hiPS-CMs during differentiation
2022, Free Radical Biology and MedicineCitation Excerpt :Mitochondria, as the powerhouse, play an important role in bioenergetics, free radical generation, calcium homeostasis, and apoptosis in an active tissue such as heart [1]. Mitochondria, encoded by nuclear and mitochondrial DNA, are the most sensitive organelles to various stimulations, including oxygen and nutrient supply, and the metabolic adaptation to the changing environment [2,3]. Mitochondria are the major source of superoxide, a primary reactive oxygen species (ROS), in eukaryotic cells [4].
Mitochondrial DNA A3243G variant-associated retinopathy: Current perspectives and clinical implications
2021, Survey of OphthalmologyAge-Related Macular Degeneration
2021, Age-Related Macular Degeneration
- 1
Present address: Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
The author was associated with the Environmental Toxicology program during the initial stages of manuscript preparation and at the present address during subsequent development and revision of the manuscript.