Mitochondrial defects in cancer (original) (raw)

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.

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.

Role of Mitochondrial Mutations in Cancer

Endocrine Pathology, 2006

A role for mitochondria in cancer causation has been implicated through identification of mutations in the mitochondrial DNA (mtDNA) and in nuclear-encoded mitochondrial genes. Although many mtDNA mutations were detected in common tumors, an unequivocal causal link between heritable mitochondrial abnormalities and cancer is provided only by the germ line mutations in the nuclear-encoded genes for succinate dehydrogenase (mitochondrial complex II) and fumarate hydratase (fumarase). The absence of evidence for highly penetrant tumors caused by inherited mtDNA mutations contrasts with the frequent occurrence of mtDNA mutations in many different tumor types. Thus, either the majority of diverse mtDNA mutations observed in tumors are not important for the process of carcinogenesis or that they play a common oncogenic role.

Mitochondrial DNA mutations in cancer - from bench to bedside

Mitochondria are cell organelles mostly known for their production of ATP through oxidative phosphorylation. As suggested over 70 years ago by O. Warburg and recently confirmed with molecular techniques, alterations in respiratory activity and mitochondrial DNA appear to be a common feature of malignant cells. Somatic mtDNA mutations have been reported in many types of cancer cells. MtDNA mutation pattern may enhance the specificity of cancer diagnostics, detection and prediction of tumor growth rate and patients’ outcome. Therefore it may be used as a molecular cancer bio-marker. Nevertheless recently published papers list a large number of mitochondrial DNA mutations in many different cancer types, but their role in cell patophysiology remains unsummarized. This review covers the consequences of mitochondrial genes mutations for human cell physiology and proliferation. We underline effects of mtDNA mutation-resulting amino acid changes in the respiratory chain proteins’ structure, and propose changes in mitochondrial protein function. Mutations are critically evaluated and interpreted in the functional context and clinical utility of molecular mitochondrial research is summarized and new perspectives for ‘mitochondrial oncology’ suggested. TABLE OF CONTENTS 1. Abstract 2. Introduction 2.1. MtDNA mutation mechanism 2.2. The role of reactive oxygen species in mitochondrial carcinogenesis 3. D-loop mutations in human cancers 3.1. Consequences for cell physiology 3.2. Clinical implications 4. tRNA genes mutations in human cancers 4.1 Consequences for cell physiology 4.2. Clinical implications 5. rRNA genes mutations 6. OXPHOS complex I genes and human cancer 6.1. Consequences for cell physiology 6.2. Clinical implications 7. OXPHOS complex III genes 7.1. Consequences for cell physiology 8. OXPHOS complex IV genes and human cancer 8.1. Consequences for cell physiology 8.2. Clinical implications 9. OXPHOS complex V genes and human cancers 9.1. Consequences for cell physiology 9.2. Clinical implications 10. Large mtDNA deletions and mtDNA depletion in human cancers 11. OXPHOS genes expression in human cancers 12. Summary and perspectives 13. Acknowledgements 14. References

A Review on the Role of Mitochondrial DNA Mutations in Cancer

Medical laboratory sciences, 2021

Mitochondria implement various cellular functions, including energy production through the electron transport chain by oxidative phosphorylation mechanism. These respiratory chains consist of several complexes and protein subunits which are encoded by nuclear and mitochondrial genes. Due to mutation susceptibility and repair limitation, more aberrations have occurred in mitochondrial DNA in comparison to nuclear DNA. Given the fact that mitochondrial DNA lacks introns, mutations almost occur in the coding sequence, which comprises a direct impact on its functions. Emerging evidence indicates that mutations in the mitochondrial DNA led to the production of reactive oxygen species, disrupted apoptosis, and tumor development. Studies reported various somatic and germline variants in mitochondrial DNA related to tumorigenesis. The D-loop region which is the starting point for replication and transcription of mitochondrial DNA is the most prevalent site of somatic mutations in solid tumors. The D-loop mutations also cause copy number variations which are gaining interest in studies of solid tumors including breast cancer, colon cancer, hepatocellular carcinomas, and prostate cancer. Most studies have reported a mitochondrial DNA reduction which subsequently prevents apoptosis and promotes metastasis. The mitochondrial DNA regionspecific haplogroups are also involved in the sequence variations due to processes such as genetic drift and adaptive selection. This review article discusses the biology and function of mitochondria and related genes. By explanation of mitochondrial dysfunction caused by different kinds of alterations, we attempt to elucidate the role of mitochondria in tumorigenesis. Prominently published articles in this field were reviewed and the role of germline and somatic mutations of mitochondrial DNA have been investigated in common cancers.

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.

Mitochondrial Abnormalities and Pathways of Cancer

2014

Mitochondrial DNA (mtDNA) depletes mainly through damaged induced by DNA replication/reading errors and reactive oxygen species (ROS). Endothelial dysfunction (ED) is a result of increased oxidative stress, resulting from electron leakage in the biochemical reactions that occur in mitochondria, and leading to inhibition of nitric oxide (NO) production from endothelial nitric oxide synthase (eNOS). Dysfunction of eNOS leads to development of multiple forms of cancers. An increased reactive oxygen species (ROS) production causes mtDNA damage contributing to ED and accelerated ageing. This review explores an insight into mechanisms of mitochondrial dysfunction in cancer.

Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer

2014

Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. Here, we analysed somatic alterations in mtDNA from 1,675 tumors. We identified 1,907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C>T and A>G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. Numbers of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria, and is fundamentally linked to mtDNA replication.