Mitochondrial genome sequencing in atherosclerosis: what's next?

Sazonova, Margarita A.; Шкурат, Т. П.; Demakova, Natalya A.; Zhelankin, Andrey V.; Баринова, В. А.; Sobenin, Igor A.; Orekhov, Alexander N.

doi:10.2174/1381612822666151112152335

Cited by 11 publications

(7 citation statements)

References 14 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

View full text Add to dashboard Cite

show abstract

“…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 know about the role of mtDNA CR mutations in development of stroke and MI [7–9,11,13,14,15,17].…”

Section: Discussionmentioning

confidence: 99%

“…Recent evidence have linked certain CVDs with specific mtDNA mutation including base substitution [6–11], deletions [12], duplications [13] and point or length heteroplasmy [14–17] both in coding [6,9,10,12,14,15] and noncoding region [6–9,11,13,16,17] of mtDNA. In particular, mtDNA mutations located in CR have a potential importance since they may influence on the regulation of the mtDNA gene expression.…”

Section: Introductionmentioning

confidence: 99%

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

Umbria¹,

Ramos²,

Aluja³

et al. 2018

Preprint

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2Recent studies associated certain type of cardiovascular disease (CVD) with 3 specific mitochondrial DNA (mtDNA) defects, mainly driven by the central role of 4 mitochondria in cellular metabolism. Considering the importance of the control region 5 (CR) on the regulation of the mtDNA gene expression, the aim of the present study was 6 to investigate the role of the mtDNA CR mutations in two CVDs: stroke and myocardial 7 infarction (MI). Both, fixed and heteroplasmy mutations of the mtDNA CR in two 8 population samples of demographically-matched case and controls, were analysed 9 using 154 stroke cases, 211 MI cases and their corresponding control individuals. 10 Significant differences were found between cases and controls, reporting the 11 m.16145G>A and m.16311T>C as a potential genetic risk factors for stroke (conditional 12 logistic regression: p=0.038 and p=0.018, respectively), whereas the m.72T>C, 13 m.73A>G and m.16356T>C could act as possible beneficial genetic factors for MI 14 (conditional logistic regression: p=0.001, p=0.009 and p=0.016, respectively). 15 Furthermore, our findings also showed a high percentage of point heteroplasmy in MI 16 controls (logistic regression: p=0.046; OR= 0.209, 95% CI [0.045-0.972]). These results 17 demonstrate the possible role of mtDNA mutations in the CR on the pathogenesis of 18 stroke and MI, and show the importance of including this regulatory region in genetic 19 association studies.Given the association between cardiovascular disease and specific mitochondrial 23 DNA (mtDNA) defects and considering the importance of the control region of this 24 genome on the regulation of mtDNA gene expression, here, we investigate the role of 25 mutations in mitochondrial DNA control region in two cardiovascular diseases: stroke 3 26 and myocardial infarction. In this study we found five mitochondrial genetic variants 27 related to cardiovascular disease, based on single nucleotide polymorphisms (SNPs), 28 which are located in the control region of mtDNA. Despite the abundance of work on 29 the role of mitochondrial DNA in relation to cardiovascular disease, little literature has 30 been published on the variation that this genome expresses in relation to this disease. 31For this reason, our study provides significant insight of the genetic variability that 32 determines normality or pathology in relation to the genetic risk of cardiovascular 33 disease. The results obtained demonstrate the possible role of mtDNA mutations in the 34 control region on the pathogenesis of stroke and myocardial infarction, and show the 35 importance of including this regulatory region in genetic association studies. 36 37 48(O H ), three conserved sequence blocks and the termination associated sequences (TAS) 49[3]. MtDNA is more susceptible than nuclear DNA to oxidative damage, probably due 50 to the lack histone complex and an inefficient DNA repair mechanisms, which may 4 51 serve as a protective barrier against external and internal noxious agents as reactive 52 oxygen species (ROS) [4]. ...

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“…Recent studies have confirmed that next-generation sequencing (NGS) could be used to detect mitochondrial gene mutations (10). NGS is found to be more efficient, more sensitive, and more accurate (11, 12).…”

Section: Discussionmentioning

confidence: 99%

Whole exome sequencing revealed a novel mutation of MT-ND5 gene in a mitochondrial cardiomyopathy pedigree: patients showed biventricular hypertrophy, hyperlactacidemia, pulmonary hypertension, decreased exercise tolerance

Zhou

Tang²,

Qin³

et al. 2018

Anatol J Cardiol

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Objective: The aim of the present study was to determine whether pathogenic mutations were present in families with mitochondrial cardiomyopathy that presented during adolescence. Methods: The proband was a 21-year-old man who presented clinically with palpitations, chest tightness, pulmonary hypertension, and limited exercise tolerance. Cardiac magnetic resonance imaging studies showed biventricular cardiac hypertrophy. We determine whether pathogenic mutations were present by whole-exome sequencing (WES) in families. Results: Screening of the family using tandem mass spectrometry showed elevated lactic acid levels, glutaric aciduria, a mildly increased glutarylcarnitine-to-octanoylcarnitine ratio, and normal blood α-glucosidase, which was consistent with a respiratory chain complex 1 metabolic disorder. We identified a novel mutation of MT-ND5 , c.1315A>G (p.Thr439Ala). Skeletal muscle biopsy histology showed predominantly ragged red fibers and few ragged blue fibers, which was consistent with mitochondrial myopathy. Conclusion: In the present study, we identified a novel mutation of MT-ND5 , c.1315A>G (p.Thr439Ala), in a family pedigree using WES.

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Mitochondrial genome sequencing in atherosclerosis: what's next?

Cited by 11 publications

References 14 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

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

Whole exome sequencing revealed a novel mutation of MT-ND5 gene in a mitochondrial cardiomyopathy pedigree: patients showed biventricular hypertrophy, hyperlactacidemia, pulmonary hypertension, decreased exercise tolerance

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