The Role of Mitochondrial DNA Mutations in Cardiovascular Diseases

Cardiovascular diseases (CVD) are one of the leading causes of morbidity and mortality worldwide. mtDNA (mitochondrial DNA) mutations are known to participate in the development and progression of some CVD. Moreover, specific types of mitochondria-mediated CVD have been discovered, such as MIEH (maternally inherited essential hypertension) and maternally inherited CHD (coronary heart disease). Maternally inherited mitochondrial CVD is caused by certain mutations in the mtDNA, which encode structural mitochondrial proteins and mitochondrial tRNA. In this review, we focus on recently identified mtDNA mutations associated with CVD (coronary artery disease and hypertension). Additionally, new data suggest the role of mtDNA mutations in Brugada syndrome and ischemic stroke, which before were considered only as a result of mutations in nuclear genes. Moreover, we discuss the molecular mechanisms of mtDNA involvement in the development of the disease.

tRNAleu A3243G Gene Mutation of Mitochondrial DNA as a Risk Factor for Diabetic Retinopathy in Type 2 Diabetes Mellitus in Bali

Introduction: Diabetic retinopathy is one of the chronic complications in patients with diabetes mellitus caused by progressive microangiopathy. Various types of risk factors can affect the occurrence of diabetic retinopathy, one of which is mitochondrial DNA mutations in the tRNAleu A3243G gene that is common in T2DM. This study was conducted with the aim to identify whether the mutation of the tRNAleu A3243G gene acts as a risk factor for diabetic retinopathy in T2DM patients in Bali. Material and Methods: This study used a case control design with 35 T2DM patients with diabetic retinopathy and 35 T2DM patients without diabetic retinopathy. The techniques used to identify these mutations are PCR and DNA sequencing. Results: Based on the results obtained, no mutations were found in the tRNAleu A3243G gene in the entire sample. Therefore, the relationship analysis of the two variables cannot be identified. Conclusions: Mutations of the tRNAleu A3243G gene that were not successfully identified in this study can be concluded not play a role as a risk factor for diabetic retinopathy. Keywords: Diabetic Retinopathy, Diabetes Mellitus, tRNAleu Gene Mutation, Mitochondrial DNA.

Somatic Mutations in Cardiovascular Disease

Advances in population-scale genomic sequencing have greatly expanded the understanding of the inherited basis of cardiovascular disease (CVD). Reanalysis of these genomic datasets identified an unexpected risk factor for CVD, somatically acquired DNA mutations. In this review, we provide an overview of somatic mutations and their contributions to CVD. We focus on the most common and well-described manifestation, clonal hematopoiesis of indeterminate potential. We also review the currently available data regarding how somatic mutations lead to tissue mosaicism in various forms of CVD, including atrial fibrillation and aortic aneurism associated with Marfan Syndrome. Finally, we highlight future research directions given current knowledge gaps and consider how technological advances will enhance the discovery of somatic mutations in CVD and management of patients with somatic mutations.

Ageing, Age-Related Cardiovascular Risk and the Beneficial Role of Natural Components Intake

Ageing, in a natural way, leads to the gradual worsening of the functional capacity of all systems and, eventually, to death. This process is strongly associated with higher metabolic and oxidative stress, low-grade inflammation, accumulation of DNA mutations and increased levels of related damage. Detrimental changes that accumulate in body cells and tissues with time raise the vulnerability to environmental challenges and enhance the risk of major chronic diseases and mortality. There are several theses concerning the mechanisms of ageing: genetic, free radical telomerase, mitochondrial decline, metabolic damage, cellular senescence, neuroendocrine theory, Hay-flick limit and membrane theories, cellular death as well as the accumulation of toxic and non-toxic garbage. Moreover, ageing is associated with structural changes within the myocardium, cardiac conduction system, the endocardium as well as the vasculature. With time, the cardiac structures lose elasticity, and fibrotic changes occur in the heart valves. Ageing is also associated with a higher risk of atherosclerosis. The results of studies suggest that some natural compounds may slow down this process and protect against age-related diseases. Animal studies imply that some of them may prolong the lifespan; however, this trend is not so obvious in humans.

New Drug Sotorasib Reduces Tumor Size and Promises to Improve and Increase Survival in Patients with Lung Tumors Caused by Specific DNA Mutations

According to the results of a global phase 2 clinical trial, the new drug stores reduce tumor size and promises to improve and increase survival in patients with lung tumors caused by specific DNA mutations. It is designed to counteract the effects of mutations that are seen in about 13% of patients with non-small cell lung adenocarcinoma (a common type of lung cancer). The Food and Drug Administration (FDA) on May 28 approved the drug as a targeted treatment for patients with small cell lung cancer whose tumors express a specific mutation called G12C in the KRAS gene. Small cell lung cancer accounts for more than 80% of lung cancers. More than 200,000 new cases of non-small cell lung cancer are diagnosed in the United States each year. Keywords: Cancer; Cells; Tissues; Tumors; Prevention; Prognosis; Diagnosis; Imaging; Screening, Treatment; Management

Significant Role of Nanoparticles as a Drug Delivery System for Cancer Treatment

According to the results of a global phase 2 clinical trial, the new drug sotorasib reduces tumor size and promises to improve and increase survival in patients with lung tumors caused by specific DNA mutations. It is designed to counteract the effects of mutations that are seen in about 13% of patients with non-small cell lung adenocarcinoma (a common type of lung cancer). The Food and Drug Administration (FDA) on May 28 approved the drug as a targeted treatment for patients with small cell lung cancer whose tumors express a specific mutation called G12C in the KRAS gene. Small cell lung cancer accounts for more than 80% of lung cancers. More than 200,000 new cases of non-small cell lung cancer are diagnosed in the United States each year. Keywords: Cancer; Cells; Tissues; Tumors; Prevention; Prognosis; Diagnosis; Imaging; Screening, Treatment; Management

Decoding Cancer Variants of Unknown Significance for Helicase–Nuclease–RPA Complexes Orchestrating DNA Repair During Transcription and Replication

All tumors have DNA mutations, and a predictive understanding of those mutations could inform clinical treatments. However, 40% of the mutations are variants of unknown significance (VUS), with the challenge being to objectively predict whether a VUS is pathogenic and supports the tumor or whether it is benign. To objectively decode VUS, we mapped cancer sequence data and evolutionary trace (ET) scores onto crystallography and cryo-electron microscopy structures with variant impacts quantitated by evolutionary action (EA) measures. As tumors depend on helicases and nucleases to deal with transcription/replication stress, we targeted helicase–nuclease–RPA complexes: (1) XPB-XPD (within TFIIH), XPF-ERCC1, XPG, and RPA for transcription and nucleotide excision repair pathways and (2) BLM, EXO5, and RPA plus DNA2 for stalled replication fork restart. As validation, EA scoring predicts severe effects for most disease mutations, but disease mutants with low ET scores not only are likely destabilizing but also disrupt sophisticated allosteric mechanisms. For sites of disease mutations and VUS predicted to be severe, we found strong co-localization to ordered regions. Rare discrepancies highlighted the different survival requirements between disease and tumor mutations, as well as the value of examining proteins within complexes. In a genome-wide analysis of 33 cancer types, we found correlation between the number of mutations in each tumor and which pathways or functional processes in which the mutations occur, revealing different mutagenic routes to tumorigenesis. We also found upregulation of ancient genes including BLM, which supports a non-random and concerted cancer process: reversion to a unicellular, proliferation-uncontrolled, status by breaking multicellular constraints on cell division. Together, these genes and global analyses challenge the binary “driver” and “passenger” mutation paradigm, support a gradient impact as revealed by EA scoring from moderate to severe at a single gene level, and indicate reduced regulation as well as activity. The objective quantitative assessment of VUS scoring and gene overexpression in the context of functional interactions and pathways provides insights for biology, oncology, and precision medicine.

Somatic mitochondrial DNA mutations in different grades of glioma

Aim: Mitochondrial DNA (mtDNA) alterations play an important role in the multistep processes of cancer development. Gliomas are among the most diagnosed brain cancer. The relationship between mtDNA alterations and different grades of gliomas are still elusive. This study aimed to elucidate the profile of somatic mtDNA mutations in different grades of gliomas and correlate it with clinical phenotype. Materials & methods: Forty histopathologically confirmed glioma tissue samples and their matched blood were collected and subjected for mtDNA sequencing. Results & conclusion: About 75% of the gliomas harbored at least one somatic mutation in the mtDNA gene, and 45% of these mutations were pathogenic. Mutations were scattered across the mtDNA genome, and the commonest nonsynonymous mutations were located at complex I and IV of the mitochondrial respiratory chain. These findings may have implication for future research to determine the mitochondrial energetics and its downstream metabolomics on gliomas.