Analysis of mitochondrial DNA heteroplasmic mutations A1555G, C3256T, T3336C, С5178А, G12315A, G13513A, G14459A, G14846А and G15059A in CHD patients with the history of myocardial infarction

Mitrofanov, Konstantin Y.; Zhelankin, Andrey V.; Шиганова, Г. М.; Sazonova, Margarita A.; Bobryshev, Yuri V.; Postnov, Anton Y.; Sobenin, Igor A.; Orekhov, Alexander N.

doi:10.1016/j.yexmp.2015.12.003

Cited by 22 publications

(17 citation statements)

References 15 publications

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“…In western countries, where the burden of CVD is growing due to effect of CV risk factors, several studies have already shown the strongly relation of the genetic factors. However, little is known about the role of mtDNA CR mutations in development of stroke and MI [7][8][9]11,[13][14][15]17 .…”

Section: Discussionmentioning

confidence: 99%

The role of control region mitochondrial DNA mutations in cardiovascular disease: stroke and myocardial infarction

Umbria

Ramos

Aluja

et al. 2020

Sci Rep

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Recent studies associated certain type of cardiovascular disease (CVD) with specific mitochondrial DnA (mtDnA) defects, mainly driven by the central role of mitochondria in cellular metabolism. considering the importance of the control region (cR) on the regulation of the mtDnA gene expression, the aim of the present study was to investigate the role of mtDnA cR mutations in two CVDs: stroke and myocardial infarction (MI). MtDNA CR mutations (both fixed and in heteroplasmy) were analysed in two demographically-matched case-control samples, using 154 stroke cases, 211 MI cases and their corresponding control individuals. Significant differences were found, reporting mutations m.16145 G > A and m.16311 T > c as potential genetic risk factors for stroke (conditional logistic regression: p = 0.038 and p = 0.018, respectively), whereas the m.72 T > C, m.73 A > G and m.16356 T > C mutations could act as possible beneficial genetic factors for MI (conditional logistic regression: p = 0.001, p = 0.009 and p = 0.016, respectively). Furthermore, our findings also showed a high percentage of point heteroplasmy in Mi controls (logistic regression: p = 0.046; OR = 0.209, 95% CI [0.045-0.972]). These results demonstrate the possible role of mtDNA mutations in the CR on the pathogenesis of stroke and Mi, and show the importance of including this regulatory region in genetic association studies. Cardiovascular disease (CVD) is one of the most widespread and common causes of death in the world. The onset and severity of these diseases are influenced by both genetic and environmental factors. Recent evidences associate mitochondrial dysfunction with several cardiovascular manifestations, mainly driven by the central role of mitochondria in cellular metabolism, particularly in energetically demanding tissues such as brain and heart 1,2. Human mitochondrial DNA (mtDNA) is 16.6-kb double-stranded circular DNA molecule that encodes for 13 electron transport chain (ETC) proteins, 2 ribosomal RNAs (rRNAs) and 22 transports RNAs (tRNAs). The control region (CR) encompasses the light and heavy strand promoters, the heavy strand origin of replication (O H), three conserved sequence blocks and the termination associated sequences (TAS) 3. MtDNA is more susceptible than nuclear DNA to oxidative damage, probably due to the lack histone complex and an inefficient DNA repair mechanisms, which may serve as a protective barrier against external and internal noxious agents as reactive oxygen species (ROS) 4. However, the hypothesis of direct damage by ROS is increasingly criticized and it is suggested that errors in mtDNA replication and repair may be the main cause of its high mutation rate (~10-fold greater than in nDNA) 5. Recent evidence have linked certain CVDs with specific mtDNA mutations including base substitutions 6-11 , deletions 12 , duplications 13 and point or length heteroplasmy 14-17 both in coding 6,9,10,12,14,15 and noncoding reg ion 6-9,11,13,16,17 of mtDNA. In particular, mtDNA mutations located in CR have a potential importanc...

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Section: Discussionmentioning

confidence: 99%

The role of control region mitochondrial DNA mutations in cardiovascular disease: stroke and myocardial infarction

Umbria

Ramos

Aluja

et al. 2020

Sci Rep

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“…In addition, total RNAs were used as negative control to exclude the contaminant of genomic DNA. All primers used were designed by [83] (Table S1). The samples were analyzed in triplicates, and relative expression levels of target genes were calculated with the 2 −ΔΔ C t method.…”

Section: Methodsmentioning

confidence: 99%

Divergent Expression Patterns and Function Implications of Four nanos Genes in a Hermaphroditic Fish, Epinephelus coioides

Sun

Wang

et al. 2017

IJMS

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Multiple nanos genes have been characterized in several fishes, but the functional implications of their various expression patterns remain unclear. In this study, we identified and characterized four nanos genes from a hermaphroditic fish orange-spotted grouper, Epinephelus coioides. Ecnanos1a and Ecnanos1b show divergent expression patterns, and the dynamic expression change of Ecnanos1a in pituitaries during sex change is associated with testis differentiation and spermatogenesis. Ecnanos2 and Ecnanos3 might be germline stem cells (GSCs) and primordial germ cells (PGCs)-specific markers, respectively. Significantly, Ecnanos3 3′-untranslated region (UTR) is necessary for PGC specific expression, where a non-canonical “GCACGTTT” sequence is required for miR-430-mediated repression of Ecnanos3 RNA. Furthermore, grouper Dead end (Dnd) can relieve miR-430 repression in PGCs by associating with a 23 bp U-rich region (URR) in Ecnanos3 3′-UTR. The current study revealed the functional association of multiple nanos genes with PGC formation and germ cell development in orange-spotted grouper, and opened up new possibilities for developing biotechnologies through utilizing the associations between Ecnanos3 and PGCs or between Ecnanos2 and GSCs in the hermaphroditic fish.

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“…Mitochondrial DNA mutations have been associated with CHD in precious studies [13][14][15]. In this study, we offer evidence of a novel mitochondrial mutation which is linked to an elevated risk of CHD.…”

Section: Discussionmentioning

confidence: 80%

Maternally inherited coronary heart disease is associated with a novel mitochondrial tRNA mutation

Zhang

et al. 2019

BMC Cardiovasc Disord

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Background: Coronary heart disease (CHD) is the most common cause of mortality globally, yet mitochondrial genetic mutations associated with CHD development remain incompletely understood. Methods: The subjects from three Chinese families with LHON underwent clinical, genetic, molecular, and biochemical evaluations. Biochemical characterizations included measuring the effects of the15910C > T mutation on tRNA Thr levels, enzymatic activity of electron transport chain complexes, membrane permeability, and the mitochondria-mediated generation of both reactive oxygen species (ROS) and adenosine triphosphate (ATP). Results: We characterize mitochondrial genetic mutations in a three-generation Chinese family exhibiting signs of maternally inherited CHD. Of the 24 different family members in this pedigree we assessed, CHD was detected in 6, with variable severity and age of first appearance. When we sequenced the mitochondrial genomes of these individuals, we found a tRNA Thr 15910C > T mutation of the Eastern Asian haplogroup M7b'c. This mutation is predicted to destabilize the strongly conserved (24C-10G) base-pairing, thereby disrupting tRNA Thr functionality. When we performed Northern blotting, we detected we observed a 37.5% reduction in tRNA Thr levels at baseline in cybrid cell lines bearing the 15910C > T mutation. When we conducted western blot analysis, we detected a~24.96% decrease in mitochondrial translation rates in these same cells. Conclusions: In the present report, Together these findings suggest a possible link between this 15910C > T tRNA Thr mutation and CHD, potentially offering new avenues for future disease intervention.

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Analysis of mitochondrial DNA heteroplasmic mutations A1555G, C3256T, T3336C, С5178А, G12315A, G13513A, G14459A, G14846А and G15059A in CHD patients with the history of myocardial infarction

Cited by 22 publications

References 15 publications

The role of control region mitochondrial DNA mutations in cardiovascular disease: stroke and myocardial infarction

The role of control region mitochondrial DNA mutations in cardiovascular disease: stroke and myocardial infarction

Divergent Expression Patterns and Function Implications of Four nanos Genes in a Hermaphroditic Fish, Epinephelus coioides

Maternally inherited coronary heart disease is associated with a novel mitochondrial tRNA mutation

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