Mitochondria and cancer (original) (raw)
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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.
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.
Relevance of mitochondrial genetics and metabolism in cancer development
Cold Spring Harbor perspectives in biology, 2013
Cancer cells are characterized in general by a decrease of mitochondrial respiration and oxidative phosphorylation, together with a strong enhancement of glycolysis, the so-called Warburg effect. The decrease of mitochondrial activity in cancer cells may have multiple reasons, related either to the input of reducing equivalents to the electron transfer chain or to direct alterations of the mitochondrial respiratory complexes. In some cases, the depression of respiratory activity is clearly the consequence of disruptive mitochondrial DNA (mtDNA) mutations and leads as a consequence to enhanced generation of reactive oxygen species (ROS). By acting both as mutagens and cellular mitogens, ROS may contribute directly to cancer progression. On the basis of our experimental evidence, we suggest a deep implication of the supercomplex organization of the respiratory chain as a missing link between oxidative stress, energy failure, and tumorigenesis. We speculate that under conditions of oxi...
Defects in mitochondrial metabolism and cancer
Cancer & Metabolism, 2014
Cancer is a heterogeneous set of diseases characterized by different molecular and cellular features. Over the past decades, researchers have attempted to grasp the complexity of cancer by mapping the genetic aberrations associated with it. In these efforts, the contribution of mitochondria to the pathogenesis of cancer has tended to be neglected. However, more recently, a growing body of evidence suggests that mitochondria play a key role in cancer. In fact, dysfunctional mitochondria not only contribute to the metabolic reprogramming of cancer cells but they also modulate a plethora of cellular processes involved in tumorigenesis. In this review, we describe the link between mutations to mitochondrial enzymes and tumor formation. We also discuss the hypothesis that mutations to mitochondrial and nuclear DNA could cooperate to promote the survival of cancer cells in an evolving metabolic landscape.
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
Human Molecular Genetics, 2009
Mitochondrial alteration has been long proposed to play a major role in tumorigenesis. Recently, mitochondrial DNA (mtDNA) mutations have been found in a variety of cancer cells. In this study, we examined the contribution of mtDNA mutation and mitochondrial dysfunction in tumorigenesis first using human cell lines carrying a frameshift at NADH dehydrogenase (respiratory complex I) subunit 5 gene (ND5); the same homoplasmic mutation was also identified in a human colorectal cancer cell line earlier. With increasing mutant ND5 mtDNA content, respiratory function including oxygen consumption and ATP generation through oxidative phosphorylation declined progressively, while lactate production and dependence on glucose increased. Interestingly, the reactive oxygen species (ROS) levels and apoptosis exhibited antagonistic pleiotropy associated with mitochondrial defects. Furthermore, the anchorage-dependence phenotype and tumor-forming capacity of cells carrying wild-type and mutant mtDNA were tested by growth assay in soft agar and subcutaneous implantation of the cells in nude mice. Surprisingly, the cell line carrying the heteroplasmic ND5 mtDNA mutation showed significantly enhanced tumor growth, while cells with homoplasmic form of the same mutation inhibited tumor formation. Similar results were obtained from the analysis of a series of mouse cell lines carrying a nonsense mutation at ND5 gene. Our results indicate that the mtDNA mutations might play an important role in the early stage of cancer development, possibly through alteration of ROS generation and apoptosis.
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.
Genetic Modification of Mitochondrial DNA in Cancer Cells
Indian Journal of Forensic Medicine & Toxicology, 2021
Mitochondria is one of the most energy source in the cells, in addition to DNA encoded to several genes which relatively associated with several disease, researchers proved the role of mitochondrial in energy demand to tumor cells in addition to mitochondrial DNA role in cancer initiation and development. The present review explained different objectives related with the mitochondrial role in tumor incidence ; these included Tumor cells energy demands, Mitochondrial Mutations redundancy and allocation, Genetic disparate natural Selection in Tumor initiation, Mitochondrial Modifications Clinical Translations in Cancer, Association Mitochondria, epigenetics and Cancer and finally Injury of Mitochondria in Cancer. The present review concluded that the most important role of mitochondrial as cells an organelles for energy suppliers to tumor cells metastasis and immorality also the mutations of mtDNA and their role in carcinogenesis were well proved in different cancer types.