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 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 Cell and animal models of mtDNA biology: progress and prospects

2007 ◽  
Vol 292 (2) ◽  
pp. C658-C669 ◽  
Author(s):  
Shaharyar M. Khan ◽  
Rafal M. Smigrodzki ◽  
Russell H. Swerdlow
Keyword(s):  
Gene Therapy ◽  
Animal Models ◽  
Human Disease ◽  
Mitochondrial Genetics ◽  
Mtdna Mutation ◽  
Mtdna Mutations ◽  
The Past ◽  
The Future ◽  
Basic Biology ◽  
Over Time

The past two decades have witnessed an evolving understanding of the mitochondrial genome’s (mtDNA) role in basic biology and disease. From the recognition that mutations in mtDNA can be responsible for human disease to recent efforts showing that mtDNA mutations accumulate over time and may be responsible for some phenotypes of aging, the field of mitochondrial genetics has greatly benefited from the creation of cell and animal models of mtDNA mutation. In this review, we critically discuss the past two decades of efforts and insights gained from cell and animal models of mtDNA mutation. We attempt to reconcile the varied and at times contradictory findings by highlighting the various methodologies employed and using human mtDNA disease as a guide to better understanding of cell and animal mtDNA models. We end with a discussion of scientific and therapeutic challenges and prospects for the future of mtDNA transfection and gene therapy.

Mitochondrial DNA Mutation, Diseases, and Nutrient-Regulated Mitophagy

2019 ◽  
Vol 39 (1) ◽  
pp. 201-226 ◽  
Author(s):  
Xuan Yang ◽  
Ruoyu Zhang ◽  
Kiichi Nakahira ◽  
Zhenglong Gu
Keyword(s):  
Mitochondrial Dna ◽  
Molecular Mechanisms ◽  
Genetic Manipulation ◽  
Wide Spectrum ◽  
Human Diseases ◽  
Nutrient Deficiencies ◽  
Mtdna Mutation ◽  
Mitochondrial Dna Mutation ◽  
Mtdna Mutations ◽  
Mitochondrial Homeostasis

A wide spectrum of human diseases, including cancer, neurodegenerative diseases, and metabolic disorders, have been shown to be associated with mitochondrial dysfunction through multiple molecular mechanisms. Mitochondria are particularly susceptible to nutrient deficiencies, and nutritional intervention is an essential way to maintain mitochondrial homeostasis. Recent advances in genetic manipulation and next-generation sequencing reveal the crucial roles of mitochondrial DNA (mtDNA) in various pathophysiological conditions. Mitophagy, a term coined to describe autophagy that targets dysfunctional mitochondria, has emerged as an important cellular process to maintain mitochondrial homeostasis and has been shown to be regulated by various nutrients and nutritional stresses. Given the high prevalence of mtDNA mutations in humans and their impact on mitochondrial function, it is important to investigate the mechanisms that regulate mtDNA mutation. Here, we discuss mitochondrial genetics and mtDNA mutations and their implications for human diseases. We also examine the role of mitophagy as a therapeutic target, highlighting how nutrients may eliminate mtDNA mutations through mitophagy.

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 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 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.

Mitochondrial DNA-related Disorders

2007 ◽  
Vol 27 (1-3) ◽  
pp. 31-37 ◽  
Author(s):  
Michelangelo Mancuso ◽  
Massimiliano Filosto ◽  
Anna Choub ◽  
Marta Tentorio ◽  
Laura Broglio ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Respiratory Chain ◽  
Nuclear Genome ◽  
Mitochondrial Diseases ◽  
Mitochondrial Respiratory Chain ◽  
Mitochondrial Genetics ◽  
Respiratory Chain Deficiency ◽  
Clinical Syndromes ◽  
Clinical Pictures

Mitochondrial diseases are a group of disorders due to a mitochondrial respiratory chain deficiency. They may depend on mitochondrial genome (mtDNA-related disorders) as well as on a nuclear genome defect (nDNA-related disorders). mtDNA-related disorders encompass an increasing number of clinical pictures associated with more than 250 different provisional or confirmed pathogenic changes in mtDNA. Although some clinical syndromes are nosologically defined, most of the cases present with polymorphous phenotypes ranging from pure myopathy to multi-system involvement. Complexity of mitochondrial genetics is in part responsible for the extreme clinical intra- and inter-familial heterogeneity of this group of diseases. In this review, we briefly report an updated classification and overview the main clinical pictures of this class of diseases.

scholarly journals Mitochondrial DNA mutations in disease and aging

2011 ◽  
Vol 193 (5) ◽  
pp. 809-818 ◽  
Author(s):  
Chan Bae Park ◽  
Nils-Göran Larsson
Keyword(s):  
Mitochondrial Dna ◽  
Oxidative Phosphorylation ◽  
Molecular Level ◽  
Mitochondrial Diseases ◽  
Mitochondrial Genetics ◽  
Replication Errors ◽  
Mtdna Mutations ◽  
Accumulated Damage ◽  
Dna Mutations ◽  
Human Pathology

The small mammalian mitochondrial DNA (mtDNA) is very gene dense and encodes factors critical for oxidative phosphorylation. Mutations of mtDNA cause a variety of human mitochondrial diseases and are also heavily implicated in age-associated disease and aging. There has been considerable progress in our understanding of the role for mtDNA mutations in human pathology during the last two decades, but important mechanisms in mitochondrial genetics remain to be explained at the molecular level. In addition, mounting evidence suggests that most mtDNA mutations may be generated by replication errors and not by accumulated damage.

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