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Mitochondrial DNA damage and repair during ischemia-reperfusion injury of the heart

Published on Jan 1, 2015in Journal of Molecular and Cellular Cardiology5.05
· DOI :10.1016/j.yjmcc.2014.11.010
Marte Bliksøen7
Estimated H-index: 7
(University of Oslo),
Anton Baysa7
Estimated H-index: 7
(University of Oslo)
+ 5 AuthorsGuro Valen30
Estimated H-index: 30
(University of Oslo)
Cite
Abstract
Abstract Ischemia–reperfusion (IR) injury of the heart generates reactive oxygen species that oxidize macromolecules including mitochondrial DNA (mtDNA). The 8-oxoguanine DNA glycosylase (OGG1) works synergistically with MutY DNA glycosylase (MYH) to maintain mtDNA integrity. Our objective was to study the functional outcome of lacking the repair enzymes OGG1 and MYH after myocardial IR and we hypothesized that OGG1 and MYH are important enzymes to preserve mtDNA and heart function after IR. Ex vivo global ischemia for 30 min followed by 10 min of reperfusion induced mtDNA damage that was removed within 60 min of reperfusion in wild-type mice. After 60 min of reperfusion the ogg1 −/− mice demonstrated increased mtDNA copy number and decreased mtDNA damage removal suggesting that OGG1 is responsible for removal of IR-induced mtDNA damage and copy number regulation. mtDNA damage was not detected in the ogg1 −/− / myh −/− , inferring that adenine opposite 8-oxoguanine is an abundant mtDNA lesion upon IR. The level and integrity of mtDNA were restored in all genotypes after 35 min of regional ischemia and six week reperfusion with no change in cardiac function. No consistent upregulation of other mitochondrial base excision repair enzymes in any of our knockout models was found. Thus repair of mtDNA oxidative base lesions may not be important for maintenance of cardiac function during IR injury in vivo. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease."
  • References (48)
  • Citations (18)
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References48
Newest
Published on Jun 1, 2012in International Journal of Cardiology3.47
Marte Bliksøen7
Estimated H-index: 7
(University of Oslo),
Lars Henrik Mariero4
Estimated H-index: 4
(University of Oslo)
+ 9 AuthorsPål Aukrust70
Estimated H-index: 70
(University of Oslo)
Published on Mar 1, 2012in DNA Repair3.71
Ruth Halsne2
Estimated H-index: 2
(Oslo University Hospital),
Ying Esbensen8
Estimated H-index: 8
(Ahus: Akershus University Hospital)
+ 4 AuthorsLars Eide19
Estimated H-index: 19
(Oslo University Hospital)
Abstract Reactive oxygen species (ROS) are formed as natural byproducts during aerobic metabolism and readily induce premutagenic base lesions in the DNA. The 8-oxoguanine DNA glycosylase (OGG1) and MutY homolog 1 (MYH) synergistically prevent mutagenesis and cancer formation in mice. Their localization in the mitochondria as well as in the nucleus suggests that mutations in mitochondrial DNA (mtDNA) contribute to the carcinogenesis in the myh −/− /ogg1 −/− double knockout mouse. In order to tes...
Jianxun Wang4
Estimated H-index: 4
,
Qianwen Wang4
Estimated H-index: 4
+ 2 AuthorsPaul N. Epstein32
Estimated H-index: 32
Cardiac failure is associated with increased levels of oxidized DNA, especially mitochondrial (mtDNA). It is not known if oxidized mtDNA contributes to cardiac dysfunction. To test if protection of mtDNA can reduce cardiac injury, we produced transgenic mice with cardiomyocyte-specific overexpression of the DNA repair enzyme 8-oxoguanine DNA glycosylase 1 (OGG1) isoform 2a. In one line of mice, the transgene increased OGG1 activity by 115% in mitochondria and by 28% in nuclei. OGG1 transgenic mi...
Published on Feb 1, 2011in Journal of Cerebral Blood Flow and Metabolism6.04
Dong Liu18
Estimated H-index: 18
(NIH: National Institutes of Health),
Deborah L. Croteau38
Estimated H-index: 38
(NIH: National Institutes of Health)
+ 8 AuthorsVilhelm A. Bohr87
Estimated H-index: 87
(NIH: National Institutes of Health)
7,8-Dihydro-8-oxoguanine DNA glycosylase (OGG1) is a major DNA glycosylase involved in base-excision repair (BER) of oxidative DNA damage to nuclear and mitochondrial DNA (mtDNA). We used OGG1-deficient (OGG1−/−) mice to examine the possible roles of OGG1 in the vulnerability of neurons to ischemic and oxidative stress. After exposure of cultured neurons to oxidative and metabolic stress levels of OGG1 in the nucleus were elevated and mitochondria exhibited fragmentation and increased levels of ...
Published on Feb 1, 2011in Journal of Bioenergetics and Biomembranes2.55
R. A. P. Costa1
Estimated H-index: 1
(State University of Campinas),
C. D. Romagna1
Estimated H-index: 1
+ 1 AuthorsN. C. Souza-Pinto1
Estimated H-index: 1
Mitochondria contain their own genome, a small circular molecule of around 16.5 kbases. The mitochondrial DNA (mtDNA) encodes for only 13 polypeptides, but its integrity is essential for mitochondrial function, as all 13 proteins are regulatory subunits of the oxidative phosphorylation complexes. Nonetheless, the mtDNA is physically associated with the inner mitochondrial membrane, where the majority of the cellular reactive oxygen species are generated. In fact, the mitochondrial DNA accumulate...
Published on Feb 1, 2011in International Journal of Cardiology3.47
Agnes Mayr29
Estimated H-index: 29
(Innsbruck Medical University),
Johannes Mair50
Estimated H-index: 50
(Innsbruck Medical University)
+ 7 AuthorsBernhard Metzler35
Estimated H-index: 35
(Innsbruck Medical University)
Abstract Aim of the study We sought to assess the relation of N-terminal brain natriuretic peptide (NT-pro BNP) determined on day 3 after onset of acute myocardial infarction (AMI) symptoms with acute and chronic infarct size and functional parameters assessed by cardiac magnetic resonance (CMR) imaging. Furthermore, we wanted to investigate its predictive value for recovery of myocardial function. Methods CMR was performed in 49 consecutive patients within 6days and in a subgroup 4 ( n =27) and...
Published on Aug 15, 2010in Free Radical Biology and Medicine5.66
Zsolt Radak49
Estimated H-index: 49
(Semmelweis University),
Istvan Boldogh41
Estimated H-index: 41
(UTMB: University of Texas Medical Branch)
Abstract The one-electron oxidation product of guanine, 8-oxo-7,8-dihydroguanine (8-oxoG), is an abundant lesion in genomic, mitochondrial, and telomeric DNA and RNA. It is considered to be a marker of oxidative stress that preferentially accumulates at the 5′ end of guanine strings in the DNA helix, in guanine quadruplexes, and in RNA molecules. 8-OxoG has a lower oxidation potential compared to guanine; thus it is susceptible to oxidation/reduction and, along with its redox products, is tradit...
Published on Aug 1, 2010in Experimental Gerontology3.08
Ricardo Gredilla5
Estimated H-index: 5
(AU: Aarhus University),
Vilhelm Bohr1
Estimated H-index: 1
(AU: Aarhus University),
Tinna Stevnsner33
Estimated H-index: 33
(AU: Aarhus University)
Mitochondrial DNA is constantly exposed to oxidative injury. Due to its location close to the main site of reactive oxygen species, the inner mitochondrial membrane, mtDNA is more susceptible than nuclear DNA to oxidative damage. The accumulation of DNA damage is thought to play a critical role in the aging process and to be particularly deleterious in post-mitotic cells. Thus, DNA repair is an important mechanism for maintenance of genomic integrity. Despite the importance of mitochondria in th...
Published on Jun 1, 2010in Neurobiology of Aging4.40
Ricardo Gredilla5
Estimated H-index: 5
(AU: Aarhus University),
Christian Garm4
Estimated H-index: 4
(AU: Aarhus University)
+ 2 AuthorsTinna Stevnsner33
Estimated H-index: 33
(AU: Aarhus University)
Aging in the brain is characterized by increased susceptibility to neuronal loss and functional decline, and mitochondrial DNA (mtDNA) mutations are thought to play an important role in these processes. Due to the proximity of mtDNA to the main sites of mitochondrial free radical generation, oxidative stress is a major source of DNA mutations in mitochondria. The base excision repair (BER) pathway removes oxidative lesions from mtDNA, thereby constituting an important mechanism to avoid accumula...
Published on May 14, 2010in Circulation Research15.86
Georgios Karamanlidis10
Estimated H-index: 10
(UW: University of Washington),
Luigino Nascimben14
Estimated H-index: 14
(Harvard University)
+ 3 AuthorsRong Tian34
Estimated H-index: 34
(UW: University of Washington)
Rationale: Mitochondrial dysfunction plays a pivotal role in the development of heart failure. Animal studies suggest that impaired mitochondrial biogenesis attributable to downregulation of the peroxisome proliferator-activated receptor γ coactivator (PGC)-1 transcriptional pathway is integral of mitochondrial dysfunction in heart failure. Objective: The study sought to define mechanisms underlying the impaired mitochondrial biogenesis and function in human heart failure. Methods and Results: W...
Cited By18
Newest
Afonso Caricati-Neto14
Estimated H-index: 14
,
Paolo Ruggero Errante1
Estimated H-index: 1
,
Francisco Sandro Menezes-Rodrigues4
Estimated H-index: 4
Ischemic heart diseases (IHD) are the leading cause of death worldwide. Although the principal form of treatment of IHD is myocardial reperfusion, the recovery of coronary blood flow after ischemia can cause severe and fatal cardiac dysfunctions, mainly due to the abrupt entry of oxygen and ionic deregulation in cardiac cells. The ability of these cells to protect themselves against injury including ischemia and reperfusion (I/R), has been termed “cardioprotection”. This protective response can ...
Published on May 8, 2019in Oxidative Medicine and Cellular Longevity4.87
Qianwen Chu (STU: Shantou University), Yanmei Zhang14
Estimated H-index: 14
(STU: Shantou University)
+ 8 AuthorsFuchun Zheng6
Estimated H-index: 6
(STU: Shantou University)
Both c-Jun N-terminal kinase (JNK) and reactive oxygen species (ROS) play important roles in myocardial ischemia/reperfusion (I/R) injury. Our previous studies suggest that N-n-butyl haloperidol iodide (F2) exerts cardioprotection by reducing ROS production and JNK activation caused by I/R. In this study, we hypothesized that there is a JNK/Sab/Src/ROS pathway in the mitochondria in H9c2 cells following hypoxia/reoxygenation (H/R) that induces oxidative stress in the mitochondria and that F2 exe...
Published on May 1, 2019in Journal of Molecular and Cellular Cardiology5.05
Jing Yang (UAB: University of Alabama at Birmingham), Jin He (UAB: University of Alabama at Birmingham)+ 10 AuthorsGlenn C. Rowe22
Estimated H-index: 22
(UAB: University of Alabama at Birmingham)
Abstract Aims The FDA-approved histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA, Vorinostat) has been shown to induce cardiomyocyte autophagy and blunt ischemia/reperfusion (I/R) injury when administered at the time of reperfusion. However, the precise mechanisms underlying the cardioprotective activity of SAHA are unknown. Mitochondrial dysfunction and oxidative damage are major contributors to myocardial apoptosis during I/R injury. We hypothesize that SAHA protects ...
Published on Feb 1, 2019in American Journal of Transplantation7.16
Maria N. Sanz1
Estimated H-index: 1
(University of Bern),
Emilie Farine2
Estimated H-index: 2
(University of Bern)
+ 10 AuthorsAnne Garnier1
Estimated H-index: 1
(Université Paris-Saclay)
Donation after circulatory death (DCD) holds great promise for improving cardiac graft availability, however concerns persist regarding injury following warm ischemia, after donor circulatory arrest, and subsequent reperfusion. Application of pre-ischemic treatments is limited for ethical reasons, thus cardioprotective strategies applied at graft procurement (reperfusion) are of particular importance in optimizing graft quality. Given the key role of mitochondria in cardiac ischemia-reperfusion ...
Published on May 1, 2018in Journal of Molecular and Cellular Cardiology5.05
Ge Zhang1
Estimated H-index: 1
(Tianjin Medical University),
Mingwei Sheng1
Estimated H-index: 1
(Tianjin Medical University)
+ 4 AuthorsZhelong Xu5
Estimated H-index: 5
(Tianjin Medical University)
Abstract Serine 727 (Ser 727 ) phosphorylation of STAT3 plays a role in the regulation of mitochondrial respiration. This study aimed to test if zinc could regulate mitochondrial respiration through phosphorylation of STAT3 at Ser 727 in the setting of ischemia/reperfusion in the heart. Under normoxic conditions, treatment of isolated rat hearts with ZnCl 2 increased cytosolic STAT3 phosphorylation at Ser 727 followed by phospho-STAT3 translocation to mitochondria. In isolated rat hearts subject...
Qun Chen31
Estimated H-index: 31
(VCU: Virginia Commonwealth University),
Fadi N. Salloum42
Estimated H-index: 42
(MCV: VCU Medical Center)
Published on Feb 1, 2018in Experimental Neurology4.56
Yundan Pan4
Estimated H-index: 4
(CSU: Central South University),
Na Wang5
Estimated H-index: 5
(CSU: Central South University)
+ 3 AuthorsZhi Ye3
Estimated H-index: 3
(CSU: Central South University)
Abstract Although the neuroprotective effects of Rac1 inhibition have been reported in various cerebral ischemic models, the molecular mechanisms of action have not yet been fully elucidated. In this study, we investigated whether the inhibition of Rac1 provided neuroprotection in a diabetic rat model of focal cerebral ischemia and hyperglycemia-exposed PC-12 cells. Intracerebroventricular administration of lentivirus expressing the Rac1 small hairpin RNA (shRNA) and specific Rac1 inhibitor NSC2...
Published on Nov 26, 2017in Spectroscopy Letters1.08
Yanbin Su1
Estimated H-index: 1
(JLU: Jilin University),
Yanwen Su2
Estimated H-index: 2
(JLU: Jilin University)
+ 5 AuthorsShuxin Li1
Estimated H-index: 1
(JLU: Jilin University)
Evidences of ultraviolet visible spectra of hydrogen sulfide scavenging trans-crotonaldehyde (TCA) induced by hydrogen peroxide through mitochondria were probed for the first time. TCA was induced by hydrogen peroxide through mitochondria. When sodium hydrosulfide as hydrogen sulfide donor, comparison with control, ultraviolet visible spectra of TCA decrease were clear. Hydrogen sulfide released by garlic was detected by ultraviolet visible spectroscopy. When garlic as hydrogen sulfide donors, t...
Published on Sep 1, 2017in Toxicology3.55
André F. Ferreira6
Estimated H-index: 6
(UC: University of Coimbra),
Teresa Cunha-Oliveira16
Estimated H-index: 16
(UC: University of Coimbra)
+ 5 AuthorsPaulo J. Oliveira50
Estimated H-index: 50
(UC: University of Coimbra)
Abstract Doxorubicin (DOX), a potent and broad-spectrum antineoplastic agent, causes an irreversible, cumulative and dose-dependent cardiomyopathy that ultimately leads to congestive heart failure. The mechanisms responsible for DOX cardiotoxicity remain poorly understood, but seem to involve mitochondrial dysfunction on several levels. Epigenetics may explain a portion of this effect. Since mitochondrial dysfunction may affect the epigenetic landscape, we hypothesize that this cardiac toxicity ...
Published on Dec 30, 2016in Medical Science Monitor1.98
Lian Jian2
Estimated H-index: 2
,
Yuan Lu2
Estimated H-index: 2
+ 1 AuthorsChengzhi Lu4
Estimated H-index: 4
Abstract BACKGROUND Cardiovascular diseases are the leading cause of death in many countries and myocardial ischemia-reperfusion (I/R) injury is the cause of many serious heart diseases. Recent reports suggested that endoplasmic reticulum (ER) stress is associated with the progress of ischemia/reperfusion (I/R) injury. In a previous study, we illustrated that 4-phenylbutyric acid (4-PBA) reduces I/R-induced cell death in vitro through inhibiting the ER stress-initiated cell apoptosis. In the pre...
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