Cancer as a "Mitochondriopathy" (original) (raw)
Related papers
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.
Current Molecular Medicine, 2007
The better part of a century has passed since Otto Warburg first hypothesized that unique phenotypic characteristics of tumor cells might be associated with an impairment in the respiratory capacity of these cells. Since then a number of distinct differences between the mitochondria of normal cells and cancer cells have been observed at the genetic, molecular, and biochemical levels. This article begins with a general overview of mitochondrial structure and function, and then outlines more specifically the metabolic and molecular alterations in mitochondria associated with human cancer and their clinical implications. Special emphasis is placed on mtDNA mutations and their potential role in carcinogenesis. The potential use of mitochondria as biomarkers for early detection of cancer, or as unique cellular targets for novel and selective anti-cancer agents is also discussed.
Virchows Archiv, 2009
The authors review the role played by mutations in mitochondrial DNA and in nuclear genes encoding mitochondrial proteins in cancer development, with an emphasis on the alterations of the oxidative phosphorylation system and glycolysis.
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.
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.
Mitochondrial DNA: The Alternative Molecular Marker for Cancer Detection and Treatment
Biology, Engineering, Medicine and Science Reports, 2016
Mitochondrion being an organelle plays a major role in many metabolic and bio synthetic pathways. Cancer is strongly associated with changes in cellular metabolism, with a characteristic metabolic shift toward aerobic glycolysis in transformed cells. The recent resurgence of interest in the study of mitochondria has come into the light due to recognition of the fact that the genetic or metabolic alterations in this organelle are causative or contributing factors in a variety of human diseases including cancer. A variety of mitochondrial dna mutations are caused by oxidative damage via ROS that are generated either endogenously during oxidative phosphorylation or by exogenous sources and other mutagens. The ability of adaptation of mitochondrial function has been recognized as crucial to the changes that occur in cancer cells. Due to the presence of this unique property of abundance and homoplasmic nature of mitochondria it makes mt DNA an attractive molecular marker of cancer. These alterations in mitochondrial structure and function might prove clinically useful either as markers for the early detection of cancer or as unique molecular sites against which novel and selective chemotherapeutic agents might be targeted. This review suggests that mitochondrion is one such target.
Mitochondrial defects in cancer
Molecular cancer, 2002
Mitochondria play important roles in cellular energy metabolism, free radical generation, and apoptosis. Defects in mitochondrial function have long been suspected to contribute to the development and progression of cancer. In this review article, we aim to provide a brief summary of our current understanding of mitochondrial genetics and biology, review the mtDNA alterations reported in various types of cancer, and offer some perspective as to the emergence of mtDNA mutations, their functional consequences in cancer development, and therapeutic implications.
Mitochondrial Subversion in Cancer
Cancer Prevention Research, 2011
Mitochondria control essential cellular activities including generation of ATP via oxidative phosphorylation. Mitochondrial DNA (mtDNA) mutations in the regulatory D-loop region and somatic mtDNA mutations are common in primary human cancers. The biological impact of a given mutation may vary, depending on the nature of the mutation and the proportion of mutant mtDNAs carried by the cell. Identification of mtDNA mutations in precancerous lesions supports their early contribution to cell transformation and cancer progression. Introduction of mtDNA mutations in transformed cells has been associated with increased ROS production and tumor growth. Studies reveal that increased and altered mtDNA plays a 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. This review offers some insight into the extent of mtDNA mutations, their functional consequences in tumorigenesis, mitochondrial therapeutics, and future clinical application. Cancer Prev Res; 4(5); 638-54. Ó2011 AACR.