Review
Mitochondrial DNA in human malignancy

https://doi.org/10.1016/S1383-5742(01)00053-9Get rights and content

Abstract

Alterations in expression of mitochondrial DNA (mtDNA)-encoded polypeptides required for oxidative phosphorylation and cellular ATP generation may be a general characteristic of cancer cells. Mitochondrial DNA has been proposed to be involved in carcinogenesis because of high susceptibility to mutations and limited repair mechanisms in comparison to nuclear DNA. Since mtDNA lacks introns, it has been suggested that most mutations will occur in coding sequences and subsequent accumulation of mutations may lead to tumor formation. The mitochondrial genome is dependent upon the nuclear genome for transcription, translation, replication and repair, but precise mechanisms for how the two genomes interact and integrate with each other are poorly understood. In solid tumors, elevated expression of mtDNA-encoded subunits of the mitochondrial electron respiratory chain may reflect mitochondrial adaptation to perturbations in cellular energy requirements. In this paper, we review mitochondrial genomic aberrations reported in solid tumors of the breast, colon, stomach, liver, kidney, bladder, head/neck and lung as well as for hematologic diseases such as leukemia, myelodysplastic syndrome and lymphoma. We include data for elevated expression of mtDNA-encoded electron respiratory chain subunits in breast, colon and liver cancers and also the mutations reported in cancers of the colon, stomach, bladder, head/neck and lung. Finally, we examine the role of reactive oxygen species (ROS) generated by mitochondria in the process of carcinogenesis.

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.

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    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.

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