scholarly journals DNA repair and mutagenesis in vertebrate mitochondria: evidence for the asymmetric DNA strand inheritance

2019 ◽  
Author(s):  
Bakhyt Matkarimov ◽  
Murat K. Saparbaev
Keyword(s):  
Nuclear Dna ◽  
Dna Damages ◽  
Mtdna Mutations ◽  
Age Related ◽  
D Loop ◽  
Exogenous Factors ◽  
Dna Strand ◽  
Cellular Dna ◽  
Heavy Strand ◽  
Orientation Bias

A variety of endogenous and exogenous factors induce chemical and structural alterations to cellular DNA, as well as errors occurring throughout DNA synthesis. These DNA damages are cytotoxic, miscoding, or both, and are believed to be at the origin of cancer and other age related diseases. A human cell, in addition to nuclear DNA, contains thousands copies of mitochondrial DNA (mtDNA), a double-stranded, circular molecule of 16,569 bp. It was proposed that mtDNA is a critical target for reactive oxygen species (ROS), by-products of the oxidative phosphorylation (OXPHOS), generated in the organelle during aerobic respiration. Indeed, oxidative damage to mtDNA are more extensive and persistent as compared to that of nuclear DNA. Although, transversions are the hallmarks of mutations induced by ROS, paradoxically, the majority of mtDNA mutations that occurred during ageing and cancer are transitions. Furthermore, these mutations exhibit a striking strand orientation bias: T→C/G→A transitions preferentially occur on the Light strand, whereas C→T/A→G on the Heavy strand of mtDNA. Here, we propose that the majority of mtDNA progenies, created after multiple rounds of DNA replication, are derived from the Heavy strand only, due to asymmetric replication of the DNA strand anchored to inner membrane via D-loop structure.

scholarly journals Mitochondrial DNA Variants and Common Diseases: A Mathematical Model for the Diversity of Age-Related mtDNA Mutations

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 608 ◽  
Author(s):  
Huanzheng Li ◽  
Jesse Slone ◽  
Lin Fei ◽  
Taosheng Huang
Keyword(s):  
Mutation Rate ◽  
Nuclear Dna ◽  
Eukaryotic Cell ◽  
Cellular Aging ◽  
Mtdna Mutation ◽  
Proliferating Cells ◽  
Mtdna Mutations ◽  
Common Diseases ◽  
Age Related ◽  
Primary Driver

The mitochondrion is the only organelle in the human cell, besides the nucleus, with its own DNA (mtDNA). Since the mitochondrion is critical to the energy metabolism of the eukaryotic cell, it should be unsurprising, then, that a primary driver of cellular aging and related diseases is mtDNA instability over the life of an individual. The mutation rate of mammalian mtDNA is significantly higher than the mutation rate observed for nuclear DNA, due to the poor fidelity of DNA polymerase and the ROS-saturated environment present within the mitochondrion. In this review, we will discuss the current literature showing that mitochondrial dysfunction can contribute to age-related common diseases such as cancer, diabetes, and other commonly occurring diseases. We will then turn our attention to the likely role that mtDNA mutation plays in aging and senescence. Finally, we will use this context to develop a mathematical formula for estimating for the accumulation of somatic mtDNA mutations with age. This resulting model shows that almost 90% of non-proliferating cells would be expected to have at least 100 mutations per cell by the age of 70, and almost no cells would have fewer than 10 mutations, suggesting that mtDNA mutations may contribute significantly to many adult onset diseases.

scholarly journals LENGTH MUTATIONS IN HUMAN MITOCHONDRIAL DNA

Genetics ◽  
1983 ◽  
Vol 104 (4) ◽  
pp. 699-711
Author(s):  
R L Cann ◽  
A C Wilson
Keyword(s):  
Nuclear Dna ◽  
Average Rate ◽  
Rapid Evolution ◽  
Human Species ◽  
Base Pairs ◽  
Human Mitochondrial Dna ◽  
Noncoding Sequences ◽  
Mitochondrial Dnas ◽  
D Loop ◽  
Length Mutations

ABSTRACT By high-resolution, restriction mapping of mitochondrial DNAs purified from 112 human individuals, we have identified 14 length variants caused by small additions and deletions (from about 6 to 14 base pairs in length). Three of the 14 length differences are due to mutations at two locations within the D loop, whereas the remaining 11 occur at seven sites that are probably within other noncoding sequences and at junctions between coding sequences. In five of the nine regions of length polymorphism, there is a sequence of five cytosines in a row, this sequence being comparatively rare in coding DNA. Phylogenetic analysis indicates that, in most of the polymorphic regions, a given length mutation has arisen several times independently in different human lineages. The average rate at which length mutations have been arising and surviving in the human species is estimated to be many times higher for noncoding mtDNA than for noncoding nuclear DNA. The mystery of why vertebrate mtDNA is more prone than nuclear DNA to evolve by point mutation is now compounded by the discovery of a similar bias toward rapid evolution by length mutation.

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.

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.

Abstract 206: Accumulation of Mitochondrial DNA Mutations Impairs Survival, Proliferation, and Differentiation of Cardiac Progenitor Cells

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Amabel M Orogo ◽  
Dieter A Kubli ◽  
Anne N Murphy ◽  
Åsa B Gustafsson
Keyword(s):  
Mitochondrial Dna ◽  
Progenitor Cells ◽  
Mitochondrial Biogenesis ◽  
Nuclear Dna ◽  
Critical Role ◽  
Chemotherapeutic Agents ◽  
Cardiac Progenitor Cells ◽  
Mtdna Mutations ◽  
Differentiation Medium ◽  
Proliferation And Differentiation

Activation and participation of cardiac progenitor cells (CPCs) in regeneration are critical for effective repair in the wake of pathologic injury. Stem cell activation and commitment involve increased energy demand and mitochondrial biogenesis. To date, little attention has been paid to the importance of mitochondria in CPC survival, proliferation and differentiation. CPC function is reduced with age but the underlying mechanism is still unclear. Mitochondrial DNA (mtDNA) is more susceptible to oxidative attacks than nuclear DNA due to its proximity to the mitochondrial respiratory chain and lack of protective histone-like proteins. With age, mtDNA accumulates mutations that can impair mitochondrial respiration and increase ROS production. In this study, we examined the effects of accumulating mtDNA mutations on CPC proliferation and survival. We have found that incubation of uncommitted c-kit+ CPCs in differentiation medium increased mitochondrial mass and expansion of the mitochondrial network, which correlated with increased cell size and expression of cardiac lineage commitment markers. Differentiation activated mitochondrial biogenesis, increased mtDNA copy number, and enhanced oxidative capacity and cellular ATP levels in CPCs. To investigate the effect of mtDNA mutations and aging on CPC survival and function, we utilized a mouse model in which a mutation in the mtDNA polymerase γ (POLG m/m ) leads to accumulation of mtDNA mutations, mitochondrial dysfunction, and accelerated aging. Isolated CPCs from hearts of 2-month old POLG m/m mice had reduced proliferation and were more susceptible to oxidative stress and chemotherapeutic agents compared to WT CPCs. The majority of POLG m/m CPCs contained fragmented mitochondria as shown by immunostaining. Incubation in differentiation medium resulted in fewer GATA-4 positive POLG m/m CPCs compared to WT CPCs. The reduced differentiation in these POLG m/m CPCs correlated with reduced PGC-1α expression and OXPHOS protein levels, suggesting that mitochondrial biogenesis is impaired. These data demonstrate that mitochondria play a critical role in CPC function, and accumulation of mtDNA mutations impairs CPC function and reduces their repair potential.

Genetic instability of multiple buds of Pinuscoulteri regenerated from tissue culture

1982 ◽  
Vol 12 (1) ◽  
pp. 93-101 ◽  
Author(s):  
Kamlesh R. Patel ◽  
Graeme P. Berlyn
Keyword(s):  
Nuclear Dna ◽  
Internal Standard ◽  
Progressive Increase ◽  
Culture Conditions ◽  
Dna Contents ◽  
Large Populations ◽  
Multiple Buds ◽  
Chicken Erythrocytes ◽  
Cellular Dna ◽  
Over Time

Embryo expiants ofPinuscoulteri D. Don. were cultured on agar media (modified from Campbell and Durzan 1975) only supplemented with 2.25 mg•L−1 of benzyl amino purine (BAP). Nuclear DNA contents were measured in cells of the embryo explants, callus, and buds regenerated from these explants, and sand-germinated seedlings. Measurements were made at weekly intervals during 6 weeks of culture. Absolute amounts of cellular DNA were determined with a microspectrophotometer using chicken erythrocytes as an internal standard. Initially, the nuclei had a DNA level between 2C and 4C with a mean of 3C. The sand-grown seedlings remained within this range, with an increased frequency of 4C nuclei in the 6-week seedlings. However, cells from callus and regenerated buds showed a progressive increase in DNA level over time. After 42 days in culture, the buds contained large populations of cells at the 8C level and a considerable number of cells with DNA levels above 8C. In addition, the nuclei showed a considerable increase in chromosomal aberrations including bridges, micronuclei, lagging chromosomes, and fragmentation. Nuclear volume also increased over time in the regenerated buds. It is therefore concluded that culture conditions, perhaps cytokinin content, increased the levels of nuclear DNA. These increased levels could be the result of polyploidy, polyteny, hyperaneuploidy, or a combination of these types of nuclear organization.

scholarly journals Maternal inheritance on reproductive traits in Brangus-Ibagé cattle

2004 ◽  
Vol 34 (4) ◽  
pp. 1163-1167 ◽  
Author(s):  
Luis Ernani Henkes ◽  
Magda Vieira Benavides ◽  
João Francisco Coelho Oliveira ◽  
José Carlos Ferrugem Moraes ◽  
Tania Azevedo Weimer
Keyword(s):  
Birth Weight ◽  
Heritability Estimate ◽  
Reproductive Traits ◽  
Direct Selection ◽  
Calving Interval ◽  
Age At First Calving ◽  
Linear Effect ◽  
Mtdna Mutations ◽  
D Loop ◽  
Additive Genetic Effects

Cytoplasmic inheritance influence on reproductive traits was investigated in the Brangus-Ibagé cattle (3/8 Nelore x 5/8 Aberdeen Angus). Additive genetic effects were responsible for 12% ± 11% of phenotypic variation observed in first calving interval, but their contribution dropped to zero when all calving intervals (CI) were considered. The heritability estimate for age at first calving (AFC, in days) was 0.19 ± 0.09. Mitochondrial lineage (MIT) had negligible effects on phenotypic variances of calving interval (0.0 ± 0.02), calf birth weight (0.0 ± 0.01), and cow weight at calving (0.0 ± 0.01). However, for the age at first calving, MIT accounted for 0.15 ± 0.07 of total variation. Cow weight at calving had a significant linear effect on CI and AFC. Three D-loop mtDNA mutations significantly affected either calving interval (T®C at sites 16,113 and 16,119) or calf birth weight (T®C at site 16,113). The C variants had decreased CI (29 and 32 days, respectively) and increased calf weight (0.6kg). Although the effects were small, direct selection for these mutation-carrier cows might improve the reproductive and developmental performance in this herd.

scholarly journals Protective Activity of C-Geranylflavonoid Analogs from Paulownia tomentosa against DNA Damage in 137Cs Irradiated AHH-1Cells

2014 ◽  
Vol 9 (9) ◽  
pp. 1934578X1400900
Author(s):  
Hyung-In Moon ◽  
Min Ho Jeong ◽  
Wol Soon Jo
Keyword(s):  
Dna Damage ◽  
Protective Effects ◽  
Strand Breaks ◽  
Human Lymphoblastoid Cell ◽  
Wide Range ◽  
Radiation Induced ◽  
Anti Oxidant ◽  
Dna Strand ◽  
Cellular Dna

Radiotherapy is an important form of treatment for a wide range of cancers, but it can damage DNA and cause adverse effects. We investigated if the diplacone analogs of P. tomentosa were radio-protective in a human lymphoblastoid cell line (AHH-1). Four geranylated flavonoids, diplacone, 3′- O-methyl-5′-hydroxydiplacone, 3′- O-methyl-5′- O-methyldiplacone and 3′- O-methyldiplacol, were tested for their antioxidant and radio-protective effects. Diplacone analogs effectively scavenged free radicals and inhibited radiation-induced DNA strand breaks in vitro. They significantly decreased levels of reactive oxygen species and cellular DNA damage in 2 Gy-irradiated AHH-1 cells. Glutathione levels and superoxide dismutase activity in irradiated AHH-1 cells increased significantly after treatment with these analogs. The enhanced biological anti-oxidant activity and radioprotective activity of diplacone analogs maintained the survival of irradiated AHH-1 cells in a clonogenic assay. These data suggest that diplacone analogs may protect healthy tissue surrounding tumor cells during radiotherapy to ensure better control of radiotherapy and allow higher doses of radiotherapy to be employed.

Increased mitochondrial DNA4977-bp deletion in catheterization laboratory workers with long-term low-dose exposure to ionizing radiation

2019 ◽  
Vol 26 (9) ◽  
pp. 976-984 ◽  
Author(s):  
Andrea Borghini ◽  
Cecilia Vecoli ◽  
Emanuela Piccaluga ◽  
Giulio Guagliumi ◽  
Eugenio Picano ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Risk Score ◽  
Nuclear Dna ◽  
High Volume ◽  
Multiple Regression Model ◽  
Mtdna Copy Number ◽  
Radiological Risk ◽  
High Exposure ◽  
Catheterization Laboratory ◽  
Mtdna Mutations

Aims Ionizing radiation may lead to mitochondrial DNA (mtDNA) mutations and changes in mtDNA content in cells, major driving mechanisms for carcinogenesis, vascular aging and neurodegeneration. The aim of this study was to investigate the possible induction of common mitochondrial deletion (mtDNA4977) and mtDNA copy number (mtDNA-CN) changes in peripheral blood of personnel working in high-volume cardiac catheterization laboratories (Cath Labs). Methods A group of 147 Cath Lab workers (median individual effective dose = 16.8 mSv, for the 41 with lifetime dosimetric record) and 74 unexposed individuals were evaluated. The occupational radiological risk score was computed for each subject on the basis of the length of employment, individual caseload and proximity to the radiation source. mtDNA4977 deletion and mtDNA-CN were assessed by using quantitative real-time polymerase chain reaction. Results Increased levels of mtDNA4977 deletion were observed in high-exposure Cath Lab workers compared with unexposed individuals ( p < 0.0001). Conversely, mtDNA-CN was significantly greater in the low-exposure workers ( p = 0.003). Occupational radiological risk score was positively correlated with mtDNA4977 deletion (Spearman's r = 0.172, p = 0.03) and inversely correlated with mtDNA-CN (Spearman's r = –0.202, p = 0.01). In multiple regression model, occupational radiological risk score emerged as significant predictor of high levels of mtDNA4977 deletion (ß coefficient = 0.236, p = 0.04). Conclusion mtDNA4977 deletion is significantly high in Cath Lab personnel. Beyond the well-recognized nuclear DNA, mtDNA damage might deserve attention as a pathogenetic molecular pathway and a potential therapeutic target of ionizing radiation damage.

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