scholarly journals Mitochondrial DNA: Hotspot for Potential Gene Modifiers Regulating Hypertrophic Cardiomyopathy

2020 ◽  
Vol 9 (8) ◽  
pp. 2349 ◽  
Author(s):  
Parisa K. Kargaran ◽  
Jared M. Evans ◽  
Sara E. Bodbin ◽  
James G. W. Smith ◽  
Timothy J. Nelson ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Hypertrophic Cardiomyopathy ◽  
Mitochondrial Genome ◽  
Treatment Options ◽  
Mitochondrial Diseases ◽  
Efficient Treatment ◽  
Novel Treatments ◽  
Sarcomeric Mutations ◽  
Patient Families ◽  
Mtdna Variants

Hypertrophic cardiomyopathy (HCM) is a prevalent and untreatable cardiovascular disease with a highly complex clinical and genetic causation. HCM patients bearing similar sarcomeric mutations display variable clinical outcomes, implying the involvement of gene modifiers that regulate disease progression. As individuals exhibiting mutations in mitochondrial DNA (mtDNA) present cardiac phenotypes, the mitochondrial genome is a promising candidate to harbor gene modifiers of HCM. Herein, we sequenced the mtDNA of isogenic pluripotent stem cell-cardiomyocyte models of HCM focusing on two sarcomeric mutations. This approach was extended to unrelated patient families totaling 52 cell lines. By correlating cellular and clinical phenotypes with mtDNA sequencing, potentially HCM-protective or -aggravator mtDNA variants were identified. These novel mutations were mostly located in the non-coding control region of the mtDNA and did not overlap with those of other mitochondrial diseases. Analysis of unrelated patients highlighted family-specific mtDNA variants, while others were common in particular population haplogroups. Further validation of mtDNA variants as gene modifiers is warranted but limited by the technically challenging methods of editing the mitochondrial genome. Future molecular characterization of these mtDNA variants in the context of HCM may identify novel treatments and facilitate genetic screening in cardiomyopathy patients towards more efficient treatment options.

Mitochondrial cardiovascular diseases

2020 ◽  
pp. 325-342
Author(s):  
Perry Elliott ◽  
Pier D. Lambiase ◽  
Dhavendra Kumar
Keyword(s):  
Mitochondrial Dna ◽  
Hypertrophic Cardiomyopathy ◽  
Cardiovascular Diseases ◽  
Mitochondrial Genome ◽  
Mitochondrial Disease ◽  
Clinical Management ◽  
Cardiac Involvement ◽  
Mitochondrial Disorders ◽  
Barth Syndrome

This chapter begins by defining the mitochondrial genome, and the subsequent assessment of suspected mitochondrial DNA (mtDNA) disorders. The incidence and prevalence of cardiac involvement in mitochondrial disorders is covered, including the probably under-reporting of this. Different cardiovascular phenotypes associated with mitochondrial disease (arrhythmias, hypertrophic cardiomyopathy, Barth syndrome etc.) are all described, and then the clinical management of the diseases are explained. As there is no fixed treatment, pharmacological regimens to avoid, and other approaches are also included.

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 Ancient mitochondrial DNA pathogenic variants putatively associated with mitochondrial disease

2020 ◽  
Author(s):  
Draga Toncheva ◽  
Dimitar Serbezov ◽  
Sena Karachanak-Yankova ◽  
Desislava Nesheva
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Disease ◽  
Novel Mutation ◽  
Mitochondrial Diseases ◽  
Type Model ◽  
Human Populations ◽  
Neolithic Period ◽  
Pathogenic Variants ◽  
Pathogenic Effect ◽  
Mtdna Variants

AbstractMitochondrial DNA variants associated with diseases are widely studied in contemporary populations, but their prevalence has not yet been investigated in ancient populations. The publicly available AmtDB database contains 1443 ancient mtDNA Eurasian genomes from different periods. The objective of this study was to use this data to establish the presence of pathogenic mtDNA variants putatively associated with mitochondrial diseases in ancient populations. The clinical significance, pathogenicity prediction and contemporary frequency of mtDNA variants were determined using online platforms. The analyzed ancient mtDNAs contain six variants designated as being “confirmed pathogenic” in modern patients. The oldest of these, m.7510T>C in the MT-TS1 gene, was found in a sample from the Neolithic period dated 5800-5400 BCE. All six have well established clinical association, and their pathogenic effect is corroborated by very low population frequencies in contemporary populations. In addition, ten variants designated as possibly or likely pathogenic were detected. The oldest of these were two variants in the MT-TD gene, m.7543A>G and m.7554G>A, from Neolithic samples dated 8205-7700 BCE. A novel mutation in contemporary populations, m.4440G>A in the MT-TM gene, is established in 12 ancient mtDNA samples from different periods ranging from 2800 BCE to 920 CE. The pathogenic effect of these possibly/likely pathogenic mutations is not yet well established, and further research is warranted. All detected mutations putatively associated with mitochondrial disease in ancient mtDNA samples are in tRNA coding genes. Most of these mutations are in a mt-tRNA type (Model 2) that is characterized by loss of D-loop/T-loop interaction. Seven mutations are located in CS-Anticodon stem, 4 are located in AS-Acceptor stem, 2 in TS-TΨC stem, and single mutations are found in DL-Dihydrouridine Loop, CL-Anticodon Loop and DS-Dihydrouridine stem. Exposing pathogenic variants in ancient human populations expands our understanding of their origin.

scholarly journals Heteroplasmic Variants of Mitochondrial DNA in Atherosclerotic Lesions of Human Aortic Intima

Biomolecules ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 455 ◽  
Author(s):  
Sobenin ◽  
Zhelankin ◽  
Khasanova ◽  
Sinyov ◽  
Medvedeva ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dna ◽  
Next Generation Sequencing ◽  
Mitochondrial Genome ◽  
Copy Number ◽  
Atherosclerotic Lesions ◽  
Mtdna Variants ◽  
Aortic Intima ◽  
And Oxidative Stress ◽  
Generation Sequencing

Mitochondrial dysfunction and oxidative stress are likely involved in atherogenesis. Since the mitochondrial genome variation can alter functional activity of cells, it is necessary to assess the presence in atherosclerotic lesions of mitochondrial DNA (mtDNA) heteroplasmic mutations known to be associated with different pathological processes and ageing. In this study, mtDNA heteroplasmy and copy number (mtCN) were evaluated in the autopsy-derived samples of aortic intima differing by the type of atherosclerotic lesions. To detect mtDNA heteroplasmic variants, next generation sequencing was used, and mtCN measurement was performed by qPCR. It was shown that mtDNA heteroplasmic mutations are characteristic for particular areas of intimal tissue; in 83 intimal samples 55 heteroplasmic variants were found; mean minor allele frequencies level accounted for 0.09, with 12% mean heteroplasmy level. The mtCN variance measured in adjacent areas of intima was high, but atherosclerotic lesions and unaffected intima did not differ significantly in mtCN values. Basing on the ratio of minor and major nucleotide mtDNA variants, we can conclude that there exists the increase in the number of heteroplasmic mtDNA variants, which corresponds to the extent of atherosclerotic morphologic phenotype.

Development of matured hiPSCs-derived 3D cardiac tissue using ERR gamma agonist and mechanical stress and application for Hypertrophic Cardiomyopathy (HCM) model

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Fujiwara ◽  
K Deguchi ◽  
Y Naka ◽  
M Sasaki ◽  
T Nishimoto ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Hypertrophic Cardiomyopathy ◽  
Mechanical Stress ◽  
Cell Size ◽  
Dna Content ◽  
Disease Model ◽  
Heart Tissue ◽  
Funding Source ◽  
Mitochondrial Dna Content ◽  
Mechanical Stretching

Abstract Introduction Tissue engineering using human induced pluripotent stem cells-derived cardiomyocytes (hiPSCs-CMs) is one of the potential tools to replicate human heart in vitro. Although there are many publications on 3 dimensional (3D) heart tissues (1), these tissues show fetal like phenotypes. For that reason, several maturation methods such as electrical stimulation and mechanical stress have been investigated (2, 3). However, these methods have been inadequate in differentiating fetal like phenotype tissue from adult tissues. Previously, we identified a novel compound, T112, which induced hiPSCs-CMs maturation from approximately 9,000 compounds using Troponin I1-EmGFP and Troponin I3-mCherry double reporter hiPSCs-CMs. This compound enhanced morphological and metabolic maturation of hiPSCs-CMs via estrogen-rerated receptor gamma activation Purpose We hypothesized that our novel compound, T112, in combination with mechanical stress could result in further maturation of 3D heart tissue. Therefore, our specific aim is to develop a novel maturation method applicable to genetic disease model of HCM using 3D heart tissue combined with T112. Methods We constructed 3D heart tissue mixed with fibroblast and double reporter hiPSCs-CMs by the hydrogel methods using Flex cell system®. We added T112 with or without mechanical stretching to 3D tissue from 7 to 15 days after 3D heart tissue was constructed. Then we measured maturation related phenotype such as sarcomere gene expression, mitochondrial DNA content and cell size. Results Similar to hiPSCs-CM, the addition of T112 to the constructed 3D heart tissue significantly increased TNNI3 mRNA compared to that of DMSO. Furthermore, T112 treated 3D heart tissue showed increased cell size and oblong shape. Next, in order to promote more maturation of 3D heart tissue, we performed mechanical stretching with the addition of T112. The combination of T112 with mechanical stretching showed higher expression of mCherry, a reporter protein for TNNI3 expression, and higher isotropy of sarcomere alignment in 3D heart tissue than that with the static condition. Furthermore, 3D heart tissue in the treatment of T112 with or without mechanical stretching showed higher mitochondrial DNA content compared to the respective DMSO controls. Interestingly, we applied this combination method to hiPSCs carrying MYH7 R719Q mutation which is known to cause hypertrophic cardiomyopathy, and the 3D heart tissue composed of cardiomyocytes derived from mutant iPSCs demonstrated increased sarcomere disarray compared to isogenic wild-type 3D heart tissue. Conclusion These results suggest that the combination of T112 and mechanical stretching promotes metabolic and structural maturation of 3D heart tissue and would be useful for creating a HCM disease model. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): T-CiRA project, Takeda Pharmaceutical Company Limited

Significance of the Carriage of Sarcomeric Mutations in Hypertrophic Cardiomyopathy in New Zealand

2021 ◽  
Vol 30 ◽  
pp. S61
Author(s):  
N. Earle ◽  
A. Winbo ◽  
J. Crawford ◽  
M. Wheeler ◽  
R. Stiles ◽  
...  
Keyword(s):  
New Zealand ◽  
Hypertrophic Cardiomyopathy ◽  
Sarcomeric Mutations

scholarly journals Epilepsy in Mitochondrial Diseases—Current State of Knowledge on Aetiology and Treatment

Children ◽  
2021 ◽  
Vol 8 (7) ◽  
pp. 532
Author(s):  
Dorota Wesół-Kucharska ◽  
Dariusz Rokicki ◽  
Aleksandra Jezela-Stanek
Keyword(s):  
Oxidative Phosphorylation ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Disease ◽  
Clinical Picture ◽  
Poor Prognosis ◽  
Treatment Options ◽  
Mitochondrial Diseases ◽  
Energy Deficit ◽  
Atp Production ◽  
Current State

Mitochondrial diseases are a heterogeneous group of diseases resulting from energy deficit and reduced adenosine triphosphate (ATP) production due to impaired oxidative phosphorylation. The manifestation of mitochondrial disease is usually multi-organ. Epilepsy is one of the most common manifestations of diseases resulting from mitochondrial dysfunction, especially in children. The onset of epilepsy is associated with poor prognosis, while its treatment is very challenging, which further adversely affects the course of these disorders. Fortunately, our knowledge of mitochondrial diseases is still growing, which gives hope for patients to improve their condition in the future. The paper presents the pathophysiology, clinical picture and treatment options for epilepsy in patients with mitochondrial disease.

scholarly journals Mitochondrial DNA Methylation and Human Diseases

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.

scholarly journals Reduced Variation in Drosophila simulans Mitochondrial DNA

Genetics ◽  
1996 ◽  
Vol 144 (4) ◽  
pp. 1519-1528
Author(s):  
J William O Ballad ◽  
Joy Hatzidakis ◽  
Timothy L Karr ◽  
Martin Kreitman
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Evolutionary Dynamics ◽  
Selective Sweep ◽  
Mitochondrial Gene ◽  
Drosophila Simulans ◽  
Dramatic Reduction ◽  
Nucleotide Variability ◽  
Pooled Samples ◽  
Mitochondrial Gene Mutation

We investigated the evolutionary dynamics of infection of a Drosophila simulans population by a maternally inherited insect bacterial parasite, Wolbachia, by analyzing nucleotide variability in three regions of the mitochondrial genome in four infected and 35 uninfected lines. Mitochondrial variability is significantly reduced compared to a noncoding region of a nuclear-encoded gene in both uninfected and pooled samples of flies, indicating a sweep of genetic variation. The selective sweep of mitochondrial DNA may have been generated by the fixation of an advantageous mitochondrial gene mutation in the mitochondrial genome. Alternatively, the dramatic reduction in mitochondrial diversity may be related to Wolbachia.

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