Mitochondrial Genome (mtDNA) and Human Diseases

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.

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

Biomolecules ◽

10.3390/biom9090499 ◽

2019 ◽

Vol 9 (9) ◽

pp. 499 ◽

Cited By ~ 1

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.

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Mitochondrial DNA Mutation, Diseases, and Nutrient-Regulated Mitophagy

Annual Review of Nutrition ◽

10.1146/annurev-nutr-082018-124643 ◽

2019 ◽

Vol 39 (1) ◽

pp. 201-226 ◽

Cited By ~ 1

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.

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

10.1101/2020.08.18.256362 ◽

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.

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

10.1101/2020.06.18.159103 ◽

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.

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Maneuvering Mitochondria for Better Understanding of Therapeutic Potential of mtDNA Mutation

10.5772/intechopen.96915 ◽

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.

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

10.1101/576165 ◽

2019 ◽

Cited By ~ 1

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms20246259 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6259 ◽

Cited By ~ 1

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.

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Mitochondrial DNA Methylation and Human Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22094594 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4594

Author(s):

Andrea Stoccoro ◽

Fabio Coppedè

Keyword(s):

Dna Methylation ◽

Mitochondrial Dna ◽

Mitochondrial Genome ◽

Nuclear Dna ◽

Epigenetic Modification ◽

Nuclear Genome ◽

Epigenetic Modifications ◽

Human Diseases ◽

Loop Region ◽

D Loop

Epigenetic modifications of the nuclear genome, including DNA methylation, histone modifications and non-coding RNA post-transcriptional regulation, are increasingly being involved in the pathogenesis of several human diseases. Recent evidence suggests that also epigenetic modifications of the mitochondrial genome could contribute to the etiology of human diseases. In particular, altered methylation and hydroxymethylation levels of mitochondrial DNA (mtDNA) have been found in animal models and in human tissues from patients affected by cancer, obesity, diabetes and cardiovascular and neurodegenerative diseases. Moreover, environmental factors, as well as nuclear DNA genetic variants, have been found to impair mtDNA methylation patterns. Some authors failed to find DNA methylation marks in the mitochondrial genome, suggesting that it is unlikely that this epigenetic modification plays any role in the control of the mitochondrial function. On the other hand, several other studies successfully identified the presence of mtDNA methylation, particularly in the mitochondrial displacement loop (D-loop) region, relating it to changes in both mtDNA gene transcription and mitochondrial replication. Overall, investigations performed until now suggest that methylation and hydroxymethylation marks are present in the mtDNA genome, albeit at lower levels compared to those detectable in nuclear DNA, potentially contributing to the mitochondria impairment underlying several human diseases.

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

Circulation ◽

10.1161/circ.142.suppl_3.17097 ◽

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.

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Modulation of mtDNA copy number ameliorates the pathological consequences of a heteroplasmic mtDNA mutation in the mouse

Science Advances ◽

10.1126/sciadv.aav9824 ◽

2019 ◽

Vol 5 (4) ◽

pp. eaav9824 ◽

Cited By ~ 15

Author(s):

R. Filograna ◽

C. Koolmeister ◽

M. Upadhyay ◽

A. Pajak ◽

P. Clemente ◽

...

Keyword(s):

Copy Number ◽

Important Determinant ◽

Threshold Level ◽

Wild Type ◽

Mtdna Copy Number ◽

Mtdna Mutation ◽

Mtdna Mutations ◽

Selective Elimination ◽

The Absolute ◽

Or Gene

Heteroplasmic mtDNA mutations typically act in a recessive way and cause mitochondrial disease only if present above a certain threshold level. We have experimentally investigated to what extent the absolute levels of wild-type (WT) mtDNA influence disease manifestations by manipulating TFAM levels in mice with a heteroplasmic mtDNA mutation in the tRNAAla gene. Increase of total mtDNA levels ameliorated pathology in multiple tissues, although the levels of heteroplasmy remained the same. A reduction in mtDNA levels worsened the phenotype in postmitotic tissues, such as heart, whereas there was an unexpected beneficial effect in rapidly proliferating tissues, such as colon, because of enhanced clonal expansion and selective elimination of mutated mtDNA. The absolute levels of WT mtDNA are thus an important determinant of the pathological manifestations, suggesting that pharmacological or gene therapy approaches to selectively increase mtDNA copy number provide a potential treatment strategy for human mtDNA mutation disease.

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