The Significance of Mitochondrial Dysfunction in Cancer (original) (raw)

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 dysfunction route as a possible biomarker and therapy target for human cancer

Biomedical Journal, 2024

Mitochondria are vital organelles found within living cells and have signalling, biosynthetic, and bioenergetic functions. Mitochondria play a crucial role in metabolic reprogramming, which is a characteristic of cancer cells and allows them to assure a steady supply of proteins, nucleotides, and lipids to enable rapid proliferation and development. Their dysregulated activities have been associated with the growth and metastasis of different kinds of human cancer, particularly ovarian carcinoma. In this review, we briefly demonstrated the modified mitochondrial function in cancer, including mutations in mtDNA, reactive oxygen species production, dynamics, apoptosis of cells, autophagy, and calcium excess to maintain cancer genesis, progression, and metastasis. Furthermore, the mitochondrial dysfunction pathway for some genomic, proteomic, and metabolomics modifications in ovarian cancer has been studied. Additionally, ovarian cancer has been linked to targeted therapies and biomarkers found through various alteration processes underlying mitochondrial dysfunction, notably targeting reactive oxygen species, metabolites, rewind metabolic pathways, and chemo-resistant ovarian carcinoma cells.

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 dysfunction in cancer

Mitochondrion, 2004

Nearly a century of scientific research has revealed a number of notable differences in the structure and function of mitochondria between normal and cancer cells, including differences in metabolic activity, molecular composition, and mtDNA sequence. This article reviews several of these differences and discusses their clinical implications, especially with regard to the use of mitochondria as biomarkers for early detection of cancer, or as unique cellular targets for novel and selective anti-cancer agents. q

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.

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.

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 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

Cancer and mitochondrial function.

Investigaciones respecto al cáncer y la función mitocondriaL- Unicauca , 2018

Se ha descrito que algunas alteraciones del metabolismo están asociadas con la pérdida de función mitocondrial en células tumorales. Aún se discute si tal pérdida se evidencia en la función o si la célula brinda máxima estabilidad a sus funciones, se requieren más estudios para conocer el comportamiento del cáncer en la mitocondria. Cuando tiene limitación de oxígeno y mutaciones en oncogenes, genes supresores de tumor y enzimas de la vía glucolítica o del metabolismo oxidativo mitocondrial, la célula tumoral permite la formación de un cáncer agresivo. Este artículo es producto de la revisión bibliográfica de la evidencia científica que se ha presentado en las últimas investigaciones respecto al cáncer y la función mitocondrial. DOI: https://doi.org/10.15446/.v66n1.59898 Sofía Isabel Freyre-Bernal, Jhan Sebastián Saavedra-Torres, Luisa Fernanda Zúñiga-Cerón, Wilmer Jair Díaz -Córdoba, María Virginia Pinzón-Fernández. Cancer and mitochondrial function. (El cáncer en la función mitocondrial) Rev. Fac. Med., Volume 66, Issue 1, p. 83-86, 2018. eISSN 2357-3848. Print ISSN 0120-0011.

Mitochondrial gateways to cancer

Molecular Aspects of Medicine, 2010

Mitochondria are required for cellular survival, yet can also orchestrate cell death. The peculiar biochemical properties of these organelles, which are intimately linked to their compartmentalized ultrastructure, provide an optimal microenvironment for multiple biosynthetic and bioenergetic pathways. Most intracellular ATP is generated by mitochondrial respiration, which also represents the most relevant source of intracellular reactive oxygen species. Mitochondria participate in a plethora of anabolic pathways, including cholesterol, cardiolipin, heme and nucleotide biosynthesis. Moreover, mitochondria integrate numerous pro-survival and pro-death signals, thereby exerting a decisive control over several biochemical cascades leading to cell death, in particular the intrinsic pathway of apoptosis. Therefore, it is not surprising that cancer cells often manifest the deregulation of one or several mitochondrial functions. The six classical hallmarks of cancer (i.e., limitless replication, self-provision of proliferative stimuli, insensitivity to antiproliferative signals, disabled apoptosis, sustained angiogenesis, invasiveness/metastatic potential), as well as other common features of tumors (i.e., avoidance of the immune response, enhanced anabolic metabolism, disabled autophagy) may directly or indirectly implicate deregulated mitochondria. In this review, we discuss several mechanisms by which mitochondria can contribute to malignant transformation and tumor progression. hydratase; HIF-1, hypoxia-inducible factor 1; HK, hexokinase; HSP, heat-shock protein; IjBa, inhibitor of jB a subunit; IjKb, IjB kinase b subunit; IM, mitochondrial inner membrane; IMS, mitochondrial intermembrane space; IP 3 R, inositol 1,4,5-trisphosphate receptor; MAPK, mitogen-activated protein kinase; MEFs, mouse embryonic fibroblasts; MMP, mitochondrial membrane permeabilization; MnSOD, manganese superoxide dismutase; MOMP, mitochondrial outer membrane permeabilization; MPT, mitochondrial permeability transition; mtCK, mitochondrial creatine kinase; OM, mitochondrial outer membrane; PBR, peripheral benzodiazepine receptor; PDGF, platelet-derived growth factor; PDH, pyruvate dehydrogenase; PDK1, PDH kinase 1; PET, positron emission tomography; PFK2, 6-phosphofructo-2-kinase; PI3K, phosphatidylinositol-3 kinase; PINK1, PTEN induced putative kinase 1; PKM2, pyruvate kinase M2 isoform; PTPC, permeability transition pore complex; RNAi, RNA interference; ROS, reactive oxygen species; SDH, succinate dehydrogenase; siRNA, small interfering RNA; Stat, signal transducer and activator of transcription; TCA, tricarboxylic acid; TGF b, transforming growth factor b; TSPO, translocator protein of 18 kDa; VDAC, voltage-dependent anion channel.