scholarly journals mtDNA in the Pathogenesis of Cardiovascular Diseases

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Lili Wang ◽  
Qianhui Zhang ◽  
Kexin Yuan ◽  
Jing Yuan
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Mitochondrial Dna ◽  
Copy Number ◽  
Heart Diseases ◽  
Mtdna Copy Number ◽  
Cardiac Inflammation ◽  
Ischemic Heart Diseases ◽  
Metabolic Functions ◽  
Underlying Mechanisms

The incidence rate of cardiovascular disease (CVD) has been increasing year by year and has become the main cause for the increase of mortality. Mitochondrial DNA (mtDNA) plays a crucial role in the pathogenesis of CVD, especially in heart failure and ischemic heart diseases. With the deepening of research, more and more evidence showed that mtDNA is related to the occurrence and development of CVD. Current studies mainly focus on how mtDNA copy number, an indirect biomarker of mitochondrial function, contributes to CVD and its underlying mechanisms including mtDNA autophagy, the effect of mtDNA on cardiac inflammation, and related metabolic functions. However, no relevant studies have been conducted yet. In this paper, we combed the current research status of the mechanism related to the influence of mtDNA on the occurrence, development, and prognosis of CVD, so as to find whether these mechanisms have something in common, or is there a correlation between each mechanism for the development of CVD?

scholarly journals Mitochondrial DNA Content Is Linked to Cardiovascular Disease Patient Phenotypes

2021 ◽  
Vol 10 (4) ◽  
Author(s):  
Ruipeng Wei, ◽  
Ying Ni, ◽  
Peter Bazeley, ◽  
Sneha Grandhi, ◽  
Janet Wang, ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Mitochondrial Dna ◽  
Copy Number ◽  
Cleveland Clinic ◽  
Disease Patient ◽  
Whole Genome Sequence ◽  
Mtdna Copy Number ◽  
Clinical Events ◽  
Mtdna Sequence ◽  
Extent Of Disease

Background We sought to determine whether mitochondrial DNA (mtDNA) content can be used as markers for 12 key phenotypes among cardiovascular disease patients, and whether these markers are valid across patients with diverse ancestries. Methods and Results DNA was collected from the peripheral blood of 996 cardiovascular disease patients at the Cleveland Clinic. The mtDNA copy number and DNA‐level variation were assessed from whole‐genome sequence. Patients were also ascertained retrospectively for histories of 10 clinical events, as well as for maximum stenosis and extent of disease at baseline. Self‐reported race and maternal ancestry inferred from mtDNA sequence were recorded. MtDNA copy number and overall mtDNA rare variant load were significantly lower in patients with histories of various adverse clinical events, and mtDNA copy number was inversely correlated with extent of disease. Strong associations were also found between absence of rare variants in the genes MT ‐ATP6 and MT‐COII and patient histories of hyperlipidemia and myocardial infarction, respectively. Importantly, associations were not ancestry dependent. Conclusions This study provides evidence that mtDNA copy number in circulation is associated with a variety of cardiovascular disease patient phenotypes. Results also suggest a protective role for some rare inherited mtDNA variants. Overall, the study supports the potential of mtDNA content and abundance as biomarkers in heart disease, in a manner that is valid across diverse ancestries.

scholarly journals Mortality Sensitivity of Cardiovascular, Cerebrovascular, and Respiratory Diseases to Warm Season Climate in Japanese Cities

Atmosphere ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1546
Author(s):  
Yukitaka Ohashi ◽  
Akari Miyata ◽  
Tomohiko Ihara
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Acute Myocardial Infarction ◽  
Respiratory Diseases ◽  
Heart Diseases ◽  
Warm Season ◽  
Respiratory Mortality ◽  
Ischemic Heart Diseases ◽  
Mean Temperature ◽  
Risk Ratios

We investigated decadal (2010–2019) cardiovascular, cerebrovascular, and respiratory mortality sensitivity to annual warm temperatures in major Japanese cities: Sapporo, Tokyo (23 wards), and Osaka. The summer mortalities (June–August) increased with the monthly mean temperature for acute myocardial infarction, other acute ischemic heart diseases, cerebral infarction, and pneumonia in the three cities. Monthly mean temperatures were an indicator of these disease mortalities in Japan. However, similar responses were not found for cardiac arrhythmia and heart failure (excluding Sapporo), subarachnoid hemorrhage, and intracerebral hemorrhage. The decadal sensitivities and risk ratios between the maximum and minimum monthly mean temperatures were calculated using a linear regression model. In Sapporo, Tokyo, and Osaka, for example, the analyses of acute myocardial infarction showed summer positive responses of 0.19–0.25, 0.13–0.18, and 0.12–0.30, respectively, as the mortality rate (per 100,000 population) per 1 °C of monthly mean temperature, which estimated increased risks (between the coolest and hottest months) of 37–65% in Sapporo, 31–42% in Tokyo, and 35–39% in Osaka.

scholarly journals Born to be young: prenatal thyroid hormones increase early-life telomere length

2020 ◽  
Author(s):  
Antoine Stier ◽  
Bin-Yan Hsu ◽  
Coline Marciau ◽  
Blandine Doligez ◽  
Lars Gustafsson ◽  
...  
Keyword(s):  
Thyroid Hormones ◽  
Telomere Length ◽  
Early Life ◽  
Copy Number ◽  
Growth Period ◽  
Postnatal Growth ◽  
Mtdna Copy Number ◽  
Underlying Mechanisms ◽  
Growth And Aging ◽  
Positive Effect

AbstractPrenatal environmental conditions can have lifelong consequences on health and aging. The underlying mechanisms remain nonetheless little understood. Thyroid hormones (THs) are important regulators of embryogenesis transferred from the mother to the embryo. In an avian model, we manipulated embryo exposure to maternal THs through egg injection and investigated the consequences on postnatal growth and aging. We first report that mitochondrial DNA (mtDNA) copy number and telomere length significantly decrease from early-life to late adulthood, thus confirming that these two molecular markers are hallmarks of aging in our wild bird model. The experimental elevation of prenatal THs levels had a transient positive effect on postnatal growth. Elevated prenatal THs had no effect on mtDNA copy number but significantly increased telomere length both soon after birth and at the end of the growth period (equivalent to offsetting ca. 4 years of post-growth telomere shortening). These findings suggest that prenatal THs have a key role in setting the ‘biological’ age at birth, and thus might influence longevity.

scholarly journals Targeting reduced mitochondrial DNA quantity as a therapeutic approach in pediatric high-grade gliomas

2019 ◽  
Vol 22 (1) ◽  
pp. 139-151 ◽  
Author(s):  
Han Shen ◽  
Man Yu ◽  
Maria Tsoli ◽  
Cecilia Chang ◽  
Swapna Joshi ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Glucose Metabolism ◽  
Mitochondrial Function ◽  
Copy Number ◽  
Pyruvate Dehydrogenase Kinase ◽  
High Grade ◽  
Mtdna Copy Number ◽  
Mitochondrial Oxidation ◽  
High Grade Gliomas

Abstract Background Despite increased understanding of the genetic events underlying pediatric high-grade gliomas (pHGGs), therapeutic progress is static, with poor understanding of nongenomic drivers. We therefore investigated the role of alterations in mitochondrial function and developed an effective combination therapy against pHGGs. Methods Mitochondrial DNA (mtDNA) copy number was measured in a cohort of 60 pHGGs. The implication of mtDNA alteration in pHGG tumorigenesis was studied and followed by an efficacy investigation using patient-derived cultures and orthotopic xenografts. Results Average mtDNA content was significantly lower in tumors versus normal brains. Decreasing mtDNA copy number in normal human astrocytes led to a markedly increased tumorigenicity in vivo. Depletion of mtDNA in pHGG cells promoted cell migration and invasion and therapeutic resistance. Shifting glucose metabolism from glycolysis to mitochondrial oxidation with the adenosine monophosphate–activated protein kinase activator AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) or the pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA) significantly inhibited pHGG viability. Using DCA to shift glucose metabolism to mitochondrial oxidation and then metformin to simultaneously target mitochondrial function disrupted energy homeostasis of tumor cells, increasing DNA damage and apoptosis. The triple combination with radiation therapy, DCA and metformin led to a more potent therapeutic effect in vitro and in vivo. Conclusions Our results suggest metabolic alterations as an onco-requisite factor of pHGG tumorigenesis. Targeting reduced mtDNA quantity represents a promising therapeutic strategy for pHGG.

264 MITOCHONDRIAL DNA COPY NUMBER IN OOCYTES OF PREPUBERTAL AND CYCLIC GILTS

2011 ◽  
Vol 23 (1) ◽  
pp. 230
Author(s):  
P. Pawlak ◽  
E. Pers-Kamczyc ◽  
D. Lechniak-Cieslak
Keyword(s):  
Mitochondrial Dna ◽  
Copy Number ◽  
Blastocyst Stage ◽  
Developmental Competence ◽  
Published Data ◽  
Mtdna Copy Number ◽  
Final Size ◽  
Domestic Species ◽  
Mitochondrial Dna Copy Number ◽  
Wide Range

In many domestic species (pig, cow, sheep), oocytes from prepubertal females show impaired quality when compared with those from adult animals. Incomplete cytoplasmic maturation is thought to be the main factor responsible for reduced developmental competence of embryos derived from prepubertal oocytes. The status of ooplasm maturation is also reflected by the copy number of mitochondrial DNA (mtDNA). Because replication of mtDNA ceases when oocytes reach their final size and occurs again at the blastocyst stage, the mtDNA copy number is a proved marker of oocyte quality in the pig (El Shourbagy et al. 2006 Reproduction 131, 233–245). The number of mtDNA copies in the grown oocyte is crucial to sustain the first embryonic divisions. To increase the rate of good-quality blastocysts, oocytes of domestic animals have been evaluated by the brilliant cresyl blue test (BCB). According to El Shourbagy et al. (2006), more competent BCB+ oocytes possess higher copy number of mtDNA (on average 222 446) than do their BCB– counterparts (115 352). However, there are no published data on the variation in mtDNA copy number in oocytes derived from ovaries of prepubertal (NCL) and cyclic (CL) gilts. Ovaries of NCL and CL gilts were collected in a local slaughterhouse. Cumulus–oocyte complexes (COC) were aspirated from nonatretic follicles 2 to 6 mm in diameter and evaluated morphologically. Only COC with a proper morphology were subjected to the BCB test. A group of non-BCB-treated COC served as control. Four groups of COC were collected: BCB+ (CL, NCL) and control (CL, NCL). Follicular cells attached to oocytes were removed by pipetting, and completely denuded gametes were individually frozen in liquid nitrogen. Analysis of the mtDNA copy number included isolation of the total DNA followed by amplification of the Cytochrome b (CYTB) gene by real-time PCR (one copy per one mitochondrial genome). Differences in mtDNA copy number among experimental groups were evaluated by Student’s t-test. To date, 30 BCB+ oocytes have been analysed individually (15 CL and 15 NCL). The analysed parameter varied in a wide range from 79 852 to 522 712 copies in CL oocytes and from 52 270 to 287 852 copies in NCL oocytes. Oocytes from cyclic gilts contained significantly more mtDNA copies (on average 267 524) than did gametes of prepubertal females (179 339; P < 0.05). The data on the mtDNA copy number in the control oocytes are currently under investigation. The preliminary results indicate that impaired oocytes quality of prepubertal gilts may be also attributed to the reduced copy number of mtDNA. This project was sponsored by MSHE Poland (grant no. 451/N-COST/2009/0).

scholarly journals Born to be young? Prenatal thyroid hormones increase early-life telomere length in wild collared flycatchers

2020 ◽  
Vol 16 (11) ◽  
pp. 20200364
Author(s):  
Antoine Stier ◽  
Bin-Yan Hsu ◽  
Coline Marciau ◽  
Blandine Doligez ◽  
Lars Gustafsson ◽  
...  
Keyword(s):  
Thyroid Hormones ◽  
Telomere Length ◽  
Early Life ◽  
Copy Number ◽  
Growth Period ◽  
Mtdna Copy Number ◽  
Cross Sectional ◽  
Telomere Shortening ◽  
Underlying Mechanisms ◽  
Age At Birth

The underlying mechanisms of the lifelong consequences of prenatal environmental condition on health and ageing remain little understood. Thyroid hormones (THs) are important regulators of embryogenesis, transferred from the mother to the embryo. Since prenatal THs can accelerate early-life development, we hypothesized that this might occur at the expense of resource allocation in somatic maintenance processes, leading to premature ageing. Therefore, we investigated the consequences of prenatal TH supplementation on potential hallmarks of ageing in a free-living avian model in which we previously demonstrated that experimentally elevated prenatal TH exposure accelerates early-life growth. Using cross-sectional sampling, we first report that mitochondrial DNA (mtDNA) copy number and telomere length significantly decrease from early-life to late adulthood, thus suggesting that these two molecular markers could be hallmarks of ageing in our wild bird model. Elevated prenatal THs had no effect on mtDNA copy number but counterintuitively increased telomere length both soon after birth and at the end of the growth period (equivalent to offsetting ca 4 years of post-growth telomere shortening). These findings suggest that prenatal THs might have a role in setting the ‘biological' age at birth, but raise questions about the nature of the evolutionary costs of prenatal exposure to high TH levels.

Profound Length Heteroplasmic Alterations in Mitochondrial DNA Control Region From Primary AML Cells: Implication of Impaired Mitochondrial Replication and Demonstration of ‘vicious cycle’ Hypothesis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3116-3116
Author(s):  
Myung-Geun Shin ◽  
Hye Ran Kim ◽  
Hyeoung-Joon Kim ◽  
Hoon Kook ◽  
Tai Ju Hwang ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Control Region ◽  
Copy Number ◽  
Regulatory Region ◽  
Mtdna Control Region ◽  
Vicious Cycle ◽  
Mtdna Copy Number ◽  
Length Heteroplasmy ◽  
Region Length ◽  
D Loop

Abstract Abstract 3116 Poster Board III-53 Mitochondrial DNA (mtDNA) control region (displacement (D)-loop including HV1 and HV2) is a non-coding region of 1124 bp (nucleotide positions, np 16 024–576), which acts as a promoter for both the heavy and light strands of mtDNA, and contains essential transcription and replication elements (Blood 2004;103:4466-77). Importantly, mutations in the D-loop regulatory region might change mtDNA replication rate by modifying the binding affinity of significant trans-activating factors (Eur J Cancer 2004;40:2519-24). Thus, length heteroplasmic alterations of mtDNA control region may be related with mitochondrial dysfunction resulting in ‘vicious cycle’ (Mol Med Today 2000;6:425-32). In an attempt to investigate profiling of mtDNA length heteroplasmic alterations in primary AML cells, we carried out a quantitative size-based PCR product separation by capillary electrophoresis (ABI 3130XL Genetic Analyzer and ABI Prism Genotyper version 3.1) using six targets (np 303-315 poly C, np 16184-16193 poly C, np 514-511 CA repeats, np 3566-3572 poly C, np 12385-12391 poly C and np 12418-12426 poly A). Length heteroplasmy was further confirmed by cloning and sequencing. Quantitative analysis of mtDNA molecules was performed using the QuantiTect SYBR Green PCR kit (Qiagen) and Rotor-Gene 3000 (Corbett Research). Forty-eight AML bone marrow samples were collected after receiving Institutional Review Board approval and informed consent. There were profound alterations of mtGI in 303 poly C, 16184 poly C and 514 CA repeats. The length heteroplasmy pattern of 303 poly C tract in the HV2 region disclosed mixture of 7C, 8C, 9C and 10C mtDNA types. In the HV2 region, length heteroplasmy in poly-C tract at np 303 - 309 exhibited 5 variant peak patterns: 7CT6C+8CT6C (50.0%), 8CT6C+9CT6C (14.0%), 8CT6C+ 9CT6C+ 10CT6C (10.4%), 9CT6C+10CT6C+11CT6C (8.3%) 9CT6C + 10CT6C + 11CT6C+12CT6C (2.1%). The length heteroplasmy pattern of 514-523 CA repeats in the HV2 region exhibited 2 variant peak patterns: CACACACACA (56.3%) and CACACACA (43.7%). In the HV1 region, length heteroplasmy in the poly-C tract at np 16184 - 16193 exhibited 9 variant peak patterns: 5CT4C+5CT3C (31.0%), 6CT4C+6CT3C (2.1%), 9C+10C+11C+12C (16.7%), 9C+10C+11C (2.1%), T4CT4C+5CT3C (4.2%), 9C+10C+11C+12C+13C (2.1%), 3CTC4C+5CT3C (2.1%), 10C+11C+12C+13C (4.2%), 8C+9C+10+11C (2.1%). Primary AML cells revealed decreased enzyme activity in respiratory chain complex I, II and III. AML cells had about a two-fold decrease in mtDNA copy number compared with normal blood mononuclear cells. Current study demonstrates that profound length heteroplasmic alterations in mtDNA control region of primary AML cells may lead to impairment of mitochondrial biogenesis (reduction of mtDNA copy number) and derangement of mitochondrial ATP synthesis. During this perturbation, mitochondria in primary AML cells might produce a large amount of reactive oxygen species, which causes the vicious cycle observed in chronic inflammatory diseases and cancers as well. Disclosures No relevant conflicts of interest to declare.

Biomarker for Benzopyrene Exposure Is Mitochondrial Mass and Mitochondrial DNA Copy in Blood Cells and Hematopoietic Tissues

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4889-4889
Author(s):  
Myung-Geun Shin ◽  
Hye-Ran Kim ◽  
Hyun-Jung Choi ◽  
Hwan-Young Kim ◽  
Dong-Kyun Han ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Mitochondrial Dna ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Copy Number ◽  
Leukemia Cells ◽  
Dependent Manner ◽  
Mtdna Copy Number ◽  
Mitochondrial Mass ◽  
Dose Dependent

Abstract Abstract 4889 Benzopyrenes are well known pollutants and carcinogens. They can intercalate into DNA and interfere transcriptions, resulting in causing various human diseases. However, biomarkers of benzopyrene toxicity have not been comprehensively studied in blood and leukemia cells. The current study was investigated to discover biomarkers for benzopyrene exposure in blood cells and leukemia cell lines. Peripheral blood, peripheral blood hematopoietic stem cell and leukemia cells (THP-1, K562, Molt-4 and HL-60) were cultured in RPMI 1640 media with adding 0, 50, 100 and 200μM of benzopyrene. Viability and apoptosis were assessed by tryptophan blue dye exclusion test and flowcytometry using annexin V. Hydrogen peroxide was measured using enzyme immunoassay. Mitochondrial mass, membrane potential and mitochondrial DNA (mtDNA) copy number were measured using MitoTracker Green, Red probes and real time PCR, respectively. The number of cell remained constant for three weeks culture. Viability of four cell lines disclosed significant decrease after two weeks of benzopyrene treatment. Apoptosis was increased in time- and dose-dependent manner after two weeks of benzopyrene treatment. Mitochondrial contents and membrane potentials were dramatically increased in three-week culture at dose dependent manner. Hydrogen peroxide level was significantly elevated after two weeks treatment of benzopyrene compared to non-benzopyrene treatment group. The number of mtDNA copy increased gradually after exposure to benzopyrene. These results indicated that increased mitochondrial mass and mtDNA copy number were biomarkers for direct exposure of benzopyrene in blood cells and hematopoietic tissues. Disclosures: No relevant conflicts of interest to declare.

Comparison between ischemic and non-ischemic heart diseases in carvedilol therapy for chronic heart failure

1999 ◽  
Vol 5 (3) ◽  
pp. 50
Author(s):  
Yoko Endo ◽  
Naoki Matsuda ◽  
Kimiharu Imamura ◽  
Katsuya Kajimoto ◽  
Haruhiko Ikegami ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Heart Diseases ◽  
Ischemic Heart ◽  
Ischemic Heart Diseases

scholarly journals Quantification of Mitochondrial DNA Deletion, Depletion, and Overreplication: Application to Diagnosis

2003 ◽  
Vol 49 (8) ◽  
pp. 1309-1317 ◽  
Author(s):  
Béatrice Chabi ◽  
Bénédicte Mousson de Camaret ◽  
Hervé Duborjal ◽  
Jean-Paul Issartel ◽  
Georges Stepien
Keyword(s):  
Mitochondrial Dna ◽  
Real Time ◽  
Southern Blot ◽  
Quantitative Pcr ◽  
Blot Analysis ◽  
Copy Number ◽  
Southern Blot Analysis ◽  
Mtdna Copy Number ◽  
Mtdna Depletion ◽  
Real Time Quantitative Pcr

Abstract Background: Many mitochondrial pathologies are quantitative disorders related to tissue-specific deletion, depletion, or overreplication of mitochondrial DNA (mtDNA). We developed an assay for the determination of mtDNA copy number by real-time quantitative PCR for the molecular diagnosis of such alterations. Methods: To determine altered mtDNA copy number in muscle from nine patients with single or multiple mtDNA deletions, we generated calibration curves from serial dilutions of cloned mtDNA probes specific to four different mitochondrial genes encoding either ribosomal (16S) or messenger (ND2, ND5, and ATPase6) RNAs, localized in different regions of the mtDNA sequence. This method was compared with quantification of radioactive signals from Southern-blot analysis. We also determined the mitochondrial-to-nuclear DNA ratio in muscle, liver, and cultured fibroblasts from a patient with mtDNA depletion and in liver from two patients with mtDNA overreplication. Results: Both methods quantified 5–76% of deleted mtDNA in muscle, 59–97% of mtDNA depletion in the tissues, and 1.7- to 4.1-fold mtDNA overreplication in liver. The data obtained were concordant, with a linear correlation coefficient (r2) between the two methods of 0.94, and indicated that quantitative PCR has a higher sensitivity than Southern-blot analysis. Conclusions: Real-time quantitative PCR can determine the copy number of either deleted or full-length mtDNA in patients with mitochondrial diseases and has advantages over classic Southern-blot analysis.

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