scholarly journals The Detection and Partial Localisation of Heteroplasmic Mutations in the Mitochondrial Genome of Patients with Diabetic Retinopathy

2019 ◽  
Vol 20 (24) ◽  
pp. 6259 ◽  
Author(s):  
Afshan N. Malik ◽  
Hannah S. Rosa ◽  
Eliane S. de Menezes ◽  
Priyanka Tamang ◽  
Zaidi Hamid ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Mitochondrial Genome ◽  
Energy Production ◽  
Mtdna Mutation ◽  
Mtdna Damage ◽  
Mtdna Mutations ◽  
High Prevalence ◽  
Severity Of The Disease ◽  
Surveyor Nuclease ◽  
Cellular Organelles

Diabetic retinopathy (DR) is a common complication of diabetes and a major cause of acquired blindness in adults. Mitochondria are cellular organelles involved in energy production which contain mitochondrial DNA (mtDNA). We previously showed that levels of circulating mtDNA were dysregulated in DR patients, and there was some evidence of mtDNA damage. In the current project, our aim was to confirm the presence of, and determine the location and prevalence of, mtDNA mutation in DR. DNA isolated from peripheral blood from diabetes patients (n = 59) with and without DR was used to amplify specific mtDNA regions which were digested with surveyor nuclease S1 to determine the presence and location of heteroplasmic mtDNA mutations were present. An initial screen of the entire mtDNA genome of 6 DR patients detected a higher prevalence of mutations in amplicon P, covering nucleotides 14,443 to 1066 and spanning the control region. Further analysis of 42 subjects showed the presence of putative mutations in amplicon P in 36% (14/39) of DR subjects and in 10% (2/20) non-DR subjects. The prevalence of mutations in DR was not related to the severity of the disease. The detection of a high-prevalence of putative mtDNA mutations within a specific region of the mitochondrial genome supports the view that mtDNA damage contributes to DR. The exact location and functional impact of these mutations remains to be determined.

scholarly journals Creation of Cybrid Cultures Containing mtDNA Mutations m.12315G>A and m.1555G>A, Associated with Atherosclerosis

Biomolecules ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 499 ◽  
Author(s):  
Margarita A. Sazonova ◽  
Vasily V. Sinyov ◽  
Anastasia I. Ryzhkova ◽  
Marina D. Sazonova ◽  
Zukhra B. Khasanova ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Drug Therapy ◽  
Mitochondrial Genome ◽  
Cell Lines ◽  
Threshold Value ◽  
Mtdna Mutation ◽  
Single Nucleotide ◽  
Mtdna Mutations ◽  
Cybrid Cell ◽  
In Cells

In the present work, a pilot creation of four cybrid cultures with high heteroplasmy level was performed using mitochondrial genome mutations m.12315G>A and m.1555G>A. According to data of our preliminary studies, the threshold heteroplasmy level of mutation m.12315G>A is associated with atherosclerosis. At the same time, for a mutation m.1555G>A, such a heteroplasmy level is associated with the absence of atherosclerosis. Cybrid cultures were created by fusion of rho0-cells and mitochondria from platelets with a high heteroplasmy level of the investigated mutations. To create rho0-cells, THP-1 culture of monocytic origin was taken. According to the results of the study, two cybrid cell lines containing mutation m.12315G>A with the heteroplasmy level above the threshold value (25% and 44%, respectively) were obtained. In addition, two cybrid cell lines containing mutation m.1555G>A with a high heteroplasmy level (24%) were obtained. Cybrid cultures with mtDNA mutation m.12315G>A can be used to model both the occurrence and development of atherosclerosis in cells and the titration of drug therapy for patients with atherosclerosis. With the help of cybrid cultures containing single nucleotide replacement of mitochondrial genome m.1555G>A, it is possible to develop approaches to the gene therapy of atherosclerosis.

scholarly journals Respiratory complex and tissue lineage drive mutational patterns in the tumor mitochondrial genome

2020 ◽  
Author(s):  
Alexander N. Gorelick ◽  
Minsoo Kim ◽  
Walid K. Chatila ◽  
Konnor La ◽  
A. Ari Hakimi ◽  
...  
Keyword(s):  
Mitochondrial Genome ◽  
Atp Synthesis ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Mtdna Mutation ◽  
Driver Genes ◽  
Cancer Driver ◽  
Translational Machinery ◽  
Synonymous Mutations ◽  
Mtdna Mutations

AbstractMitochondrial DNA (mtDNA) encodes essential protein subunits and translational machinery for four distinct complexes of oxidative phosphorylation (OXPHOS). Using repurposed whole-exome sequencing data, we demonstrate that pathogenic mtDNA mutations arise in tumors at a rate comparable to the most common cancer driver genes. We identify OXPHOS complexes as critical determinants shaping somatic mtDNA mutation patterns across tumor lineages. Loss-of-function mutations accumulate at an elevated rate specifically in Complex I, and often arise at specific homopolymeric hotspots. In contrast, Complex V is depleted of all non-synonymous mutations, suggesting that mutations directly impacting ATP synthesis are under negative selection. Both common truncating mutations and rarer missense alleles are associated with a pan-lineage transcriptional program, even in cancer types where mtDNA mutations are comparatively rare. Pathogenic mutations of mtDNA are associated with substantial increases in overall survival of colorectal adenocarcinoma patients, demonstrating a clear functional relationship between genotype and phenotype. The mitochondrial genome is therefore frequently and functionally disrupted across many cancers, with significant implications for patient stratification, prognosis and therapeutic development.

scholarly journals Maladaptive nutrient signalling sustains the m.3243A>G mtDNA mutation

2020 ◽  
Author(s):  
Chih-Yao Chung ◽  
Kritarth Singh ◽  
Vassilios N Kotiadis ◽  
Jee Hwan Ahn ◽  
Lida Kabir ◽  
...  
Keyword(s):  
Mitochondrial Genome ◽  
Lactic Acidosis ◽  
Treatment Options ◽  
Disease Phenotype ◽  
Wild Type ◽  
Mtdna Mutation ◽  
Potential Therapeutic Target ◽  
Mtdna Mutations ◽  
Cellular Bioenergetics ◽  
Clinical Conditions

ABSTRACTMutations of the mitochondrial genome (mtDNA) cause a range of profoundly debilitating clinical conditions for which treatment options are limited. Most mtDNA diseases show heteroplasmy - tissues express both wild-type and mutant mtDNA. The relationships between specific mtDNA mutations, heteroplasmy, disease phenotype and severity are poorly understood. We have extensively characterised changes in bioenergetic, metabolomic, lipidomic and RNAseq profiles in heteroplasmic patient-derived cells carrying the m.3243A>G mtDNA mutation, the cause of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). These studies reveal that the mutation promotes upregulation of the PI3K-Akt-mTORC1 axis in patient-derived cells and tissues. Remarkably, pharmacological inhibition of PI3K, Akt, or mTORC1 activated mitophagy, reduced mtDNA mutant load and rescued cellular bioenergetics cell-autonomously. The rescue was prevented by inhibition of mitophagy. These findings suggest that activation of the PI3K-Akt-mTORC1 axis is maladaptive and represents a potential therapeutic target for people suffering from the consequences of the m.3243A>G mutation.

scholarly journals Mitochondrial Genome (mtDNA) and Human Diseases

2021 ◽  
Vol 38 (4) ◽  
pp. 317-325
Author(s):  
Ronnie L. Davidson
Keyword(s):  
Mitochondrial Genome ◽  
Genetic Diseases ◽  
Human Diseases ◽  
Repair System ◽  
Technological Advancement ◽  
Mtdna Mutation ◽  
Maternal Line ◽  
Mtdna Mutations ◽  
Multiple Phenotypes ◽  
Critical Components

Mitochondria not only provide necessary energy for cells, but more importantly, they participate in the regulation of various biological functions and activities of cells. As one of the critical components of the body’s genome, mitochondrial genome (mtDNA) is the key to cell bioenergetics and genetics. However, since no protection of histones and a complete self-repair system, mtDNA is extremely prone to mutate. Human diseases caused by mtDNA mutations are only transmitted through the maternal line. The same phenotype can come from multiple mtDNA mutations, and the same mtDNA mutation can lead to multiple phenotypes. This is the major reason that makes the diagnosis and identification of mtDNA genetic diseases difficult. Meanwhile, mtDNA mutations may be the culprit involved in mediating the aging and tumorigenesis. Currently, no effective therapeutics for diseases caused by mtDNA mutations, but with the deepening of research and technological advancement, it is promising that breakthroughs in the diagnosis and treatment of mitochondrial-related diseases in the near future.

scholarly journals Maneuvering Mitochondria for Better Understanding of Therapeutic Potential of mtDNA Mutation

2021 ◽  
Author(s):  
Sanket Tembe
Keyword(s):  
Mitochondrial Genome ◽  
Ethical Issues ◽  
Therapeutic Potential ◽  
Genetic Manipulation ◽  
Mitochondrial Diseases ◽  
Mitochondrial Genetics ◽  
Mtdna Mutation ◽  
Genetic Etiology ◽  
Mtdna Mutations ◽  
Good Potential

Heterogeneity of mitochondrial diseases in terms of genetic etiology and clinical management makes their diagnosis challenging. Mitochondrial genome, basic mitochondrial genetics, common mutations, and their correlation with human diseases is well-established now and advances in sequencing is accelerating the molecular diagnostics of mitochondrial diseases. Major research focus now is on development of mtDNA intervention techniques like mtDNA gene editing, transfer of exogenous genes (sometimes even entire mtDNA) that would compensate for mtDNA mutations responsible for mitochondrial dysfunction. Although these genetic manipulation techniques have good potential for treatment of mtDNA diseases, research on such mitochondrial manipulation fosters ethical issues. The present chapter starts with an introduction to the factors that influence the clinical features of mitochondrial diseases. Advancement in treatments for mitochondrial diseases are then discussed followed by a note on methods for preventing transmission of these diseases.

scholarly journals PINK1 and parkin shape the organism-wide distribution of a deleterious mitochondrial genome

2019 ◽  
Author(s):  
Arnaud Ahier ◽  
Nadia Cummins ◽  
Chuan-Yang Dai ◽  
Jürgen Götz ◽  
Steven Zuryn
Keyword(s):  
Nervous System ◽  
Caenorhabditis Elegans ◽  
Mitochondrial Genome ◽  
Wide Distribution ◽  
Causal Link ◽  
Mtdna Mutation ◽  
Ubiquitin Protein Ligase ◽  
Mtdna Mutations ◽  
Somatic Tissues ◽  
Multiple Species

AbstractIn multiple species, certain tissue types are prone to acquiring greater loads of mitochondrial genome (mtDNA) mutations relative to others, however the mechanisms that drive these heteroplasmy differences are unknown. We found that the conserved PTEN-induced putative kinase (PINK1/PINK-1) and the E3 ubiquitin-protein ligase parkin (PDR-1), which are required for mitochondrial autophagy (mitophagy), underlie stereotyped differences in heteroplasmy of a deleterious mitochondrial genome mutation (ΔmtDNA) between major somatic tissues types in Caenorhabditis elegans. We demonstrate that tissues prone to accumulating ΔmtDNA have lower mitophagy responses than those with low mutation levels, such as neurons. Moreover, we show that ΔmtDNA heteroplasmy increases when proteotoxic species that are associated with neurodegenerative disease and mitophagy inhibition are overexpressed in the nervous system. Together, these results suggest that PINK1 and parkin drive organism-wide patterns of heteroplasmy and provide evidence of a causal link between proteotoxicity, mitophagy, and mtDNA mutation levels in neurons.

scholarly journals Antiviral, Antibacterial, Antifungal, and Antiparasitic Properties of Propolis: A Review

Foods ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1360
Author(s):  
Felix Zulhendri ◽  
Kavita Chandrasekaran ◽  
Magdalena Kowacz ◽  
Munir Ravalia ◽  
Krishna Kripal ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Antioxidant Status ◽  
Energy Production ◽  
Mechanisms Of Action ◽  
Host Cells ◽  
Physical Barrier ◽  
Inflammatory Signaling ◽  
Replication Process ◽  
Comprehensive Review ◽  
Cellular Organelles

Propolis is a complex phytocompound made from resinous and balsamic material harvested by bees from flowers, branches, pollen, and tree exudates.Humans have used propolis therapeutically for centuries. The aim of this article is to provide comprehensive review of the antiviral, antibacterial, antifungal, and antiparasitic properties of propolis. The mechanisms of action of propolis are discussed. There are two distinct impacts with regards to antimicrobial and anti-parasitic properties of propolis, on the pathogens and on the host. With regards to the pathogens, propolis acts by disrupting the ability of the pathogens to invade the host cells by forming a physical barrier and inhibiting enzymes and proteins needed for invasion into the host cells. Propolis also inhibits the replication process of the pathogens. Moreover, propolis inhibits the metabolic processes of the pathogens by disrupting cellular organelles and components responsible for energy production. With regard to the host, propolis functions as an immunomodulator. It upregulates the innate immunity and modulates the inflammatory signaling pathways. Propolis also helps maintain the host’s cellular antioxidant status. More importantly, a small number of human clinical trials have demonstrated the efficacy and the safety of propolis as an adjuvant therapy for pathogenic infections.

scholarly journals Plasma microRNA signature associated with retinopathy in patients with type 2 diabetes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Donato Santovito ◽  
Lisa Toto ◽  
Velia De Nardis ◽  
Pamela Marcantonio ◽  
Rossella D’Aloisio ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Vision Loss ◽  
External Validation ◽  
Diabetic Patients ◽  
Disease Biomarkers ◽  
Response To Stress ◽  
Severity Of The Disease ◽  
Plasma Microrna

AbstractDiabetic retinopathy (DR) is a leading cause of vision loss and disability. Effective management of DR depends on prompt treatment and would benefit from biomarkers for screening and pre-symptomatic detection of retinopathy in diabetic patients. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression which are released in the bloodstream and may serve as biomarkers. Little is known on circulating miRNAs in patients with type 2 diabetes (T2DM) and DR. Here we show that DR is associated with higher circulating miR-25-3p (P = 0.004) and miR-320b (P = 0.011) and lower levels of miR-495-3p (P < 0.001) in a cohort of patients with T2DM with DR (n = 20), compared with diabetic subjects without DR (n = 10) and healthy individuals (n = 10). These associations persisted significant after adjustment for age, gender, and HbA1c. The circulating levels of these miRNAs correlated with severity of the disease and their concomitant evaluation showed high accuracy for identifying DR (AUROC = 0.93; P < 0.001). Gene ontology analysis of validated targets revealed enrichment in pathways such as regulation of metabolic process (P = 1.5 × 10–20), of cell response to stress (P = 1.9 × 10–14), and development of blood vessels (P = 2.7 × 10–14). Pending external validation, we anticipate that these miRNAs may serve as putative disease biomarkers and highlight novel molecular targets for improving care of patients with diabetic retinopathy.

Abstract 17097: Non-Synonymous Mitochondrial DNA Variants Are Common in Myocardial Tissue of Heart Failure Patients

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Pappu Ananya ◽  
Michael Binder ◽  
Yang Wanjun ◽  
Rebecca McClellan ◽  
Brittney Murray ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mitochondrial Dna ◽  
Nuclear Dna ◽  
Left Ventricular ◽  
Individual Risk ◽  
Myocardial Tissue ◽  
Mtdna Mutation ◽  
Mtdna Mutations ◽  
Ventricular Tissue ◽  
Mtdna Variants

Introduction: Mitochondrial heart disease due to pathogenic mitochondrial DNA (mtDNA) mutations can present as hypertrophic or dilated cardiomyopathy, ventricular arrhythmias and conduction disease. It is estimated that the mutation rate of mtDNA is 10 to 20-fold higher than that of nuclear DNA genes due to damage from reactive oxygen species released as byproducts during oxidative phosphorylation. When a new mtDNA mutation arises, it creates an intracellular heteroplasmic mixture of mutant and normal mtDNAs, called heteroplasmy. Heteroplasmy levels can vary in various tissues and examining mtDNA variants in blood may not be representative for the heart. The frequency of pathogenic mtDNA variants in myocardial tissues in unknown. Hypothesis: Human ventricular tissue may contain mtDNA mutations which can lead to alterations in mitochondrial function and increase individual risk for heart failure. Methods: Mitochondrial DNA was isolated from 61 left ventricular myocardial samples obtained from failing human hearts at the time of transplantation. mtDNA was sequenced with 23 primer pairs. In silico prediction of non-conservative missense variants was performed via PolyPhen-2. Heteroplasmy levels of variants predicted to be pathogenic were quantified using allele-specific ARMS-PCR. Results: We identified 21 mtDNA non-synonymous variants predicted to be pathogenic in 17 hearts. Notably, one heart contained four pathogenic mtDNA variants (ATP6: p.M104; ND5: p.P265S; ND4: p.N390S and p.L445F). Heteroplasmy levels exceeded 90% for all four variants in myocardial tissue and were significantly lower in blood. No pathogenic mtDNA variants were identified in 44 hearts. Hearts with mtDNA mutations had higher levels of myocardial GDF-15 (growth differentiation factor-15; 6.2±2.3 vs. 1.3±0.18, p=0.045), an established serum biomarker in various mitochondrial diseases. Conclusions: Non-synonymous mtDNA variants predicted to be pathogenic are common in human left ventricular tissue and may be an important modifier of the heart failure phenotype. Future studies are necessary to correlate myocardial mtDNA mutations with cardiovascular outcomes and to assess whether serum GDF-15 allows identifying patients with myocardial mtDNA mutations.

scholarly journals Gambaran Kualitas Hidup pada Pasien Diabetik Retinopati Berdasarkan Tingkat Keparahan Visus

2020 ◽  
Vol 10 (2) ◽  
pp. 105
Author(s):  
Novita Dhewi Ikakusumawati ◽  
Dewi Magistasari ◽  
Novena Adi Yuhara ◽  
Tri Murti Andayani ◽  
Supanji Supanji ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Visual Acuity ◽  
Diabetic Retinopathy ◽  
Utility Score ◽  
Microvascular Complications ◽  
Cross Sectional ◽  
Number Of Patients ◽  
High Prevalence ◽  
Anxiety Depression

Diabetic retinopathy (DR) is one of the microvascular complications of diabetes mellitus (DM) which incidence increases with the high prevalence of DM. The presence of these complications will affect quality of life, especially vision-related. The purpose of this study was to determine the quality of life in RD patients assessed using the VFQ-25 and EQ-5D questionnaires, and to determine the of quality of life based on the visual acuity (VA) severity. This study was an observational study in outpatient with diabetic retinopathy during October 2018 – Januari 2019 period, in RSUP dr. Sardjito and RS Mata Dr. YAP, Yogyakarta. The design of this study was cross sectional which observed quality of life and vision. Quality of life was measured by specific for vision instrument (NEI-VFQ-25)  and  generic instrument  (EQ-5D-5L). The number of patients in this study were 100 patients with an average age of 55 years, the most frequent type of RD was 84% proliferative RD. The average quality of life scores in RD patients measured using the VFQ-25 and EQ-5D utility questionnaires were 64.1 ± 16.2 and 0.61 ± 0.24, respectively. Based on VFQ-25, the most affected subscales were driving, dependence, and role difficulties subscale. Meanwhile, domains that have the most problems with the EQ-5D were pain / discomfort and anxiety / depression (78%). The total VFQ-25 score decreased with increasing visual severity, i.e. normal / mild (n = 19) 73.50 ± 15.08; moderate (n = 15) 68.14 ± 15.33; and severe (n = 66) 60.48 ± 15.64. The EQ-5D utility score showed a similar pattern, with scores of 0.66 ± 0.27 (normal / mild); 0.65 ± 0.22 (medium); and 0.59 ± 0.24 (severe); respectively. The higher severity of visual acuity so the quality of life become lower.

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