Mitochondrial DNA (mtDNA) variants in the European haplogroups HV, JT, and U do not have a major role in schizophrenia

2014 ◽  
Vol 165 (7) ◽  
pp. 607-617 ◽  
Author(s):  
Helena Torrell ◽  
Antonio Salas ◽  
Nerea Abasolo ◽  
Constanza Morén ◽  
Glòria Garrabou ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mtdna Variants ◽  
European Haplogroups

The champions' mitochondria: is it genetically determined? A review on mitochondrial DNA and elite athletic performance

2011 ◽  
Vol 43 (13) ◽  
pp. 789-798 ◽  
Author(s):  
Nir Eynon ◽  
María Morán ◽  
Ruth Birk ◽  
Alejandro Lucia
Keyword(s):  
Mitochondrial Dna ◽  
Endurance Exercise ◽  
Current Knowledge ◽  
Geographic Origin ◽  
Aerobic Performance ◽  
East African ◽  
Athletic Status ◽  
The Status ◽  
Genetically Determined ◽  
Mtdna Variants

Aerobic ATP generation by the mitochondrial respiratory oxidative phosphorylation system (OXPHOS) is a vital metabolic process for endurance exercise. Notably, mitochondrial DNA (mtDNA) codifies 13 of the 83 polypeptides implied in the respiratory chain. As such, there is a strong rationale for identifying an association between mtDNA variants and “aerobic” (endurance) exercise phenotypes. The aim of this review is to summarize current knowledge on the association between mtDNA, nuclear genes involved in mitochondriogenesis, and elite endurance athletic status. Several studies in nonathletic people have demonstrated an association between certain mtDNA lineages and aerobic performance, characterized by maximal oxygen uptake (V̇o2max). Whether mtDNA haplogroups are also associated with the status of being an elite endurance athlete is more controversial, with differences between studies arising from the different ethnic backgrounds of the athletic cohorts (Caucasian of mixed geographic origin, Asiatic, or East African).

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 Case Report: Identification of a Novel Variant (m.8909T>C) of Human Mitochondrial ATP6 Gene and Its Functional Consequences on Yeast ATP Synthase

Life ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 215
Author(s):  
Qiuju Ding ◽  
Róża Kucharczyk ◽  
Weiwei Zhao ◽  
Alain Dautant ◽  
Shutian Xu ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Atp Synthase ◽  
Atp Synthesis ◽  
Single Individual ◽  
Loss Of Function ◽  
Mtdna Mutations ◽  
Atp6 Gene ◽  
Novel Variant ◽  
Functional Consequences ◽  
Mtdna Variants

With the advent of next generation sequencing, the list of mitochondrial DNA (mtDNA) mutations identified in patients rapidly and continuously expands. They are frequently found in a limited number of cases, sometimes a single individual (as with the case herein reported) and in heterogeneous genetic backgrounds (heteroplasmy), which makes it difficult to conclude about their pathogenicity and functional consequences. As an organism amenable to mitochondrial DNA manipulation, able to survive by fermentation to loss-of-function mtDNA mutations, and where heteroplasmy is unstable, Saccharomyces cerevisiae is an excellent model for investigating novel human mtDNA variants, in isolation and in a controlled genetic context. We herein report the identification of a novel variant in mitochondrial ATP6 gene, m.8909T>C. It was found in combination with the well-known pathogenic m.3243A>G mutation in mt-tRNALeu. We show that an equivalent of the m.8909T>C mutation compromises yeast adenosine tri-phosphate (ATP) synthase assembly/stability and reduces the rate of mitochondrial ATP synthesis by 20–30% compared to wild type yeast. Other previously reported ATP6 mutations with a well-established pathogenicity (like m.8993T>C and m.9176T>C) were shown to have similar effects on yeast ATP synthase. It can be inferred that alone the m.8909T>C variant has the potential to compromise human health.

scholarly journals Analysis of Mitochondrial DNA Polymorphisms in the Human Cell Lines HepaRG and SJCRH30

2019 ◽  
Vol 20 (13) ◽  
pp. 3245 ◽  
Author(s):  
Matthew J. Young ◽  
Anitha D. Jayaprakash ◽  
Carolyn K. J. Young
Keyword(s):  
Mitochondrial Dna ◽  
Cell Lines ◽  
Human Cell ◽  
Cell Types ◽  
Dna Polymorphisms ◽  
Reference Sequence ◽  
Sequencing Analysis ◽  
Human Cell Lines ◽  
Mtdna Sequences ◽  
Mtdna Variants

The mitochondrial DNA (mtDNA) sequences of two commonly used human cell lines, HepaRG and SJCRH30, were determined. HepaRG originates from a liver tumor obtained from a patient with hepatocarcinoma and hepatitis C while SJCRH30 originates from a rhabdomyosarcoma patient tumor. In comparison to the revised Cambridge Reference Sequence, HepaRG and SJCRH30 mtDNA each contain 14 nucleotide variations. In addition to an insertion of a cytosine at position 315 (315insC), the mtDNA sequences from both cell types share six common polymorphisms. Heteroplasmic variants were identified in both cell types and included the identification of the 315insC mtDNA variant at 42 and 75% heteroplasmy in HepaRG and SJCRH30, respectively. Additionally, a novel heteroplasmic G13633A substitution in the HepaRG ND5 gene was detected at 33%. Previously reported cancer-associated mtDNA variants T195C and T16519C were identified in SJCRH30, both at homoplasmy (100%), while HepaRG mtDNA harbors a known prostate cancer-associated T6253C substitution at near homoplasmy, 95%. Based on our sequencing analysis, HepaRG mtDNA is predicted to lie within haplogroup branch H15a1 while SJCRH30 mtDNA is predicted to localize to H27c. The catalog of polymorphisms and heteroplasmy reported here should prove useful for future investigations of mtDNA maintenance in HepaRG and SJCRH30 cell lines.

scholarly journals Mitochondrial DNA Mutation Detection by Electrospray Mass Spectrometry

2007 ◽  
Vol 53 (2) ◽  
pp. 195-203 ◽  
Author(s):  
Yun Jiang ◽  
Thomas A Hall ◽  
Steven A Hofstadler ◽  
Robert K Naviaux
Keyword(s):  
Mass Spectrometry ◽  
Mitochondrial Dna ◽  
Rflp Analysis ◽  
Endocrine Disorders ◽  
Ion Cyclotron Resonance ◽  
Accurate Identification ◽  
Mtdna Mutations ◽  
Fticr Ms ◽  
Pcr Rflp ◽  
Mtdna Variants

Abstract Background: Mitochondrial DNA (mtDNA) mutations cause a large spectrum of clinically important neurodegenerative, neuromuscular, cardiovascular, and endocrine disorders. We describe the novel application of electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR MS) to the rapid and accurate identification of pathogenic mtDNA variants. Methods: In a blinded study, we used ESI-FTICR MS to analyze 24 unrelated samples of total cellular DNA containing 12 mtDNA variants and compared the results with those obtained by conventional PCR-restriction fragment length polymorphism (PCR-RFLP) analysis and gel electrophoresis. Results: From the 24-sample blinded panel, we correctly identified 12 of the samples as bearing an mtDNA variant and found the remaining 12 samples to have no pathogenic variants. The correlation coefficient between the 2 methods for mtDNA variant detection was 1.0; there were no false positives or false negatives in this sample set. In addition, the ESI-FTICR method identified 4 single-nucleotide polymorphisms (SNP) that had previously been missed by standard PCR-RFLP analysis. Conclusions: ESI-FTICR MS is a rapid, sensitive, and accurate method for the identification and quantification of mtDNA mutations and SNPs.

scholarly journals What cost mitochondria? The maintenance of functional mitochondrial DNA within and across generations

2014 ◽  
Vol 369 (1646) ◽  
pp. 20130438 ◽  
Author(s):  
Duur K. Aanen ◽  
Johannes N. Spelbrink ◽  
Madeleine Beekman
Keyword(s):  
Mitochondrial Dna ◽  
Somatic Growth ◽  
Mtdna Mutations ◽  
Specific Effects ◽  
Age Related ◽  
Mtdna Replication ◽  
Mtdna Evolution ◽  
Selection For ◽  
Male Specific ◽  
Mtdna Variants

The peculiar biology of mitochondrial DNA (mtDNA) potentially has detrimental consequences for organismal health and lifespan. Typically, eukaryotic cells contain multiple mitochondria, each with multiple mtDNA genomes. The high copy number of mtDNA implies that selection on mtDNA functionality is relaxed. Furthermore, because mtDNA replication is not strictly regulated, within-cell selection may favour mtDNA variants with a replication advantage, but a deleterious effect on cell fitness. The opportunities for selfish mtDNA mutations to spread are restricted by various organism-level adaptations, such as uniparental transmission, germline mtDNA bottlenecks, germline selection and, during somatic growth, regular alternation between fusion and fission of mitochondria. These mechanisms are all hypothesized to maintain functional mtDNA. However, the strength of selection for maintenance of functional mtDNA progressively declines with age, resulting in age-related diseases. Furthermore, organismal adaptations that most probably evolved to restrict the opportunities for selfish mtDNA create secondary problems. Owing to predominantly maternal mtDNA transmission, recombination among mtDNA from different individuals is highly restricted or absent, reducing the scope for repair. Moreover, maternal inheritance precludes selection against mtDNA variants with male-specific effects. We finish by discussing the consequences of life-history differences among taxa with respect to mtDNA evolution and make a case for the use of microorganisms to experimentally manipulate levels of selection.

scholarly journals Tinnitus in patients with hearing loss due to mitochondrial DNA pathogenic variants

2018 ◽  
Vol 275 (8) ◽  
pp. 1979-1985 ◽  
Author(s):  
Urszula Lechowicz ◽  
Agnieszka Pollak ◽  
Danuta Raj-Koziak ◽  
Beata Dziendziel ◽  
Piotr Henryk Skarżyński ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Mitochondrial Dna ◽  
Visual Analogue Scale ◽  
Analogue Scale ◽  
Medical Problem ◽  
Polish Population ◽  
Pathogenic Variants ◽  
Individual Perception ◽  
Characteristic Features ◽  
Mtdna Variants

Abstract Purpose Tinnitus described as individual perception of phantom sound constitutes a significant medical problem and has become an essential subject of many studies conducted worldwide. In the study, we aimed to examine the prevalence of tinnitus among Polish hearing loss (HL) patients with identified mitochondrial DNA (mtDNA) variants. Methods Among the selected group of unrelated HL patients with known mtDNA pathogenic variants, two questionnaires were conducted, i.e. Tinnitus Handicap Inventory translated into Polish (THI-POL) and Visual Analogue Scale (VAS) for measuring subjectively perceived tinnitus loudness, distress, annoyance and possibility of coping with this condition (VASs). Pathogenic mtDNA variants were detected with real-time PCR and sequencing of the whole mtDNA. Results This is the first extensive tinnitus characterization using THI-POL and VASs questionnaires in HL patients due to mtDNA variants. We have established the prevalence of tinnitus among the studied group at 23.5%. We found that there are no statistically significant differences in the prevalence of tinnitus and its characteristic features between HL patients with known HL mtDNA variants and the general Polish population. In Polish HL patients with tinnitus, m.7511T>C was significantly more frequent than in patients without tinnitus. We observed that the prevalence of tinnitus is lower in Polish patients with m.1555A>G as compared to other available data. Conclusions Our data suggest that the mtDNA variants causative of HL may affect tinnitus development but this effect seems to be ethnic-specific.

scholarly journals EPID-10. MITOCHONDRIAL DNA SEQUENCE VARIATION AND RISK OF GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii80-ii80
Author(s):  
Claudine Samanic ◽  
Jamie Teer ◽  
Zachary Thompson ◽  
Jordan Creed ◽  
Louis Nabors ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Adult Brain ◽  
European Ancestry ◽  
Inverse Association ◽  
Increased Risk ◽  
Mtdna Sequence ◽  
The Us ◽  
Glioma Risk ◽  
The Uk ◽  
Mtdna Variants

Abstract Malignant gliomas are the most common primary adult brain tumors, with poor prognosis and ill-defined etiology. Mitochondrial DNA (mtDNA) sequence variants and haplogroups have been linked with certain cancers, but research on glioma is lacking. We examined the association of germline mtDNA variants and haplogroups with glioma risk in 1,654 glioma cases and 1,065 controls from a US case-control study, and 427 glioma cases and 1,541 controls from the UK Biobank, all genotyped using the UKBiobank array with 276 tiled mtDNA variants. The analysis was restricted to participants of European ancestry, and risk of glioblastoma (GBM) and lower grade glioma (LGG) was examined separately. Distribution of mitochondrial haplogroups (H/HV,I,J,K,R,T,U,V,W,X) were similar in both study populations, with 46.4% and 48.1% of controls in the US and UK studies respectively, identified as H/HV, the most common haplogroup. In the US study there was an inverse association between haplogroup W and glioma (OR=0.43, 95%CI: 0.23–0.79) when compared with the H/HV haplogroup, which was not seen in the UK study (OR=1.10, 95%CI: 0.49–2.49). In the US study, a significant inverse association was observed with the previously reported mtDNA variant m.14798T > C (PMID: 31323957), resulting in the amino acid substitution F18L, for LGG (OR=0.73; 95%CI: 0.53–0.99) though not for GBM (OR=0.86; 95%CI: 0.66–1.11). In the UK study, the F18L substitution was associated with an increased risk of GBM (OR=1.48; 95%CI: 1.07–2.04), and no association was observed for LGG (OR=0.95; 95%CI: 0.53–1.68). Among cases in the US study with isocitrate dehydrogenase 1 (IDH1) status available (747 gliomas), a nonsignificant inverse association of the F18L substitution was observed in glioma cases with wild type (OR=0.72; 95%CI: 0.52–1.01) but not mutant (OR=1.08; 95%CI: 0.70–1.69) IDH1. No other common mtDNA variant (minor allele > 5%) was associated with glioma risk in either study. These associations merit further study.

scholarly journals The Role of Mitochondrial DNA Variation in Drug Response: A Systematic Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Samantha W. Jones ◽  
Amy L. Ball ◽  
Amy E. Chadwick ◽  
Ana Alfirevic
Keyword(s):  
Systematic Review ◽  
Mitochondrial Dna ◽  
Drug Response ◽  
Drug Efficacy ◽  
Review Of The Literature ◽  
Inclusion Criteria ◽  
Mtdna Variation ◽  
Pubmed Database ◽  
Mtdna Variants ◽  
The Impact

Background: The triad of drug efficacy, toxicity and resistance underpins the risk-benefit balance of all therapeutics. The application of pharmacogenomics has the potential to improve the risk-benefit balance of a given therapeutic via the stratification of patient populations based on DNA variants. A growth in the understanding of the particulars of the mitochondrial genome, alongside the availability of techniques for its interrogation has resulted in a growing body of literature examining the impact of mitochondrial DNA (mtDNA) variation upon drug response.Objective: To critically evaluate and summarize the available literature, across a defined period, in a systematic fashion in order to map out the current landscape of the subject area and identify how the field may continue to advance.Methods: A systematic review of the literature published between January 2009 and December 2020 was conducted using the PubMed database with the following key inclusion criteria: reference to specific mtDNA polymorphisms or haplogroups, a core objective to examine associations between mtDNA variants and drug response, and research performed using human subjects or human in vitro models.Results: Review of the literature identified 24 articles reporting an investigation of the association between mtDNA variant(s) and drug efficacy, toxicity or resistance that met the key inclusion criteria. This included 10 articles examining mtDNA variations associated with antiretroviral therapy response, 4 articles examining mtDNA variants associated with anticancer agent response and 4 articles examining mtDNA variants associated with antimicrobial agent response. The remaining articles covered a wide breadth of medications and were therefore grouped together and referred to as “other.”Conclusions: Investigation of the impact of mtDNA variation upon drug response has been sporadic to-date. Collective assessment of the associations identified in the articles was inconclusive due to heterogeneous methods and outcomes, limited racial/ethnic groups, lack of replication and inadequate statistical power. There remains a high degree of idiosyncrasy in drug response and this area has the potential to explain variation in drug response in a clinical setting, therefore further research is likely to be of clinical benefit.

scholarly journals New Insights Into Mitochondrial DNA Reconstruction and Variant Detection in Ancient Samples

2021 ◽  
Vol 12 ◽  
Author(s):  
Maria Angela Diroma ◽  
Alessandra Modi ◽  
Martina Lari ◽  
Luca Sineo ◽  
David Caramelli ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Iron Age ◽  
Comprehensive Evaluation ◽  
Nuclear Genome ◽  
Sequencing Technologies ◽  
Almost All ◽  
Mtdna Variants ◽  
First Time ◽  
Adna Analysis ◽  
Ancient Remains

Ancient DNA (aDNA) studies are frequently focused on the analysis of the mitochondrial DNA (mtDNA), which is much more abundant than the nuclear genome, hence can be better retrieved from ancient remains. However, postmortem DNA damage and contamination make the data analysis difficult because of DNA fragmentation and nucleotide alterations. In this regard, the assessment of the heteroplasmic fraction in ancient mtDNA has always been considered an unachievable goal due to the complexity in distinguishing true endogenous variants from artifacts. We implemented and applied a computational pipeline for mtDNA analysis to a dataset of 30 ancient human samples from an Iron Age necropolis in Polizzello (Sicily, Italy). The pipeline includes several modules from well-established tools for aDNA analysis and a recently released variant caller, which was specifically conceived for mtDNA, applied for the first time to aDNA data. Through a fine-tuned filtering on variant allele sequencing features, we were able to accurately reconstruct nearly complete (>88%) mtDNA genome for almost all the analyzed samples (27 out of 30), depending on the degree of preservation and the sequencing throughput, and to get a reliable set of variants allowing haplogroup prediction. Additionally, we provide guidelines to deal with possible artifact sources, including nuclear mitochondrial sequence (NumtS) contamination, an often-neglected issue in ancient mtDNA surveys. Potential heteroplasmy levels were also estimated, although most variants were likely homoplasmic, and validated by data simulations, proving that new sequencing technologies and software are sensitive enough to detect partially mutated sites in ancient genomes and discriminate true variants from artifacts. A thorough functional annotation of detected and filtered mtDNA variants was also performed for a comprehensive evaluation of these ancient samples.

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