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

Published on Jan 1, 2015in Journal of Molecular and Cellular Cardiology5.055
· DOI :10.1016/j.yjmcc.2014.11.010
Marte Bliksøen7
Estimated H-index: 7
(University of Oslo),
Anton Baysa8
Estimated H-index: 8
(University of Oslo)
+ 5 AuthorsGuro Valen31
Estimated H-index: 31
(University of Oslo)
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 (20)
📖 Papers frequently viewed together
6 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
#1Marte Bliksøen (University of Oslo)H-Index: 7
#2Lars Henrik Mariero (University of Oslo)H-Index: 4
Last. Leif Erik VingeH-Index: 22
view all 12 authors...
55 CitationsSource
#1Ruth Halsne (Oslo University Hospital)H-Index: 2
#2Ying Esbensen (Ahus: Akershus University Hospital)H-Index: 9
Last. Lars Eide (Oslo University Hospital)H-Index: 20
view all 7 authors...
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 test this hypot...
24 CitationsSource
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...
27 CitationsSource
#1R. A. P. Costa (State University of Campinas)H-Index: 1
#2C. D. RomagnaH-Index: 1
Last. N. C. Souza-PintoH-Index: 1
view all 4 authors...
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...
28 CitationsSource
#1Dong Liu (NIH: National Institutes of Health)H-Index: 19
#2Deborah L. Croteau (NIH: National Institutes of Health)H-Index: 36
Last. Mark P. Mattson (NIH: National Institutes of Health)H-Index: 179
view all 11 authors...
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 ...
71 CitationsSource
#1Agnes Mayr (Innsbruck Medical University)H-Index: 14
#2Johannes Mair (Innsbruck Medical University)H-Index: 51
Last. Bernhard Metzler (Innsbruck Medical University)H-Index: 37
view all 10 authors...
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...
57 CitationsSource
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...
77 CitationsSource
#1Ricardo Gredilla (AU: Aarhus University)H-Index: 5
#2Vilhelm A. Bohr (AU: Aarhus University)H-Index: 1
Last. Tinna Stevnsner (AU: Aarhus University)H-Index: 34
view all 3 authors...
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...
99 CitationsSource
#1Ricardo Gredilla (AU: Aarhus University)H-Index: 5
#2Christian Garm (AU: Aarhus University)H-Index: 4
Last. Tinna Stevnsner (AU: Aarhus University)H-Index: 34
view all 5 authors...
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...
50 CitationsSource
#1Georgios Karamanlidis (UW: University of Washington)H-Index: 10
#2Luigino Nascimben (Harvard University)H-Index: 15
Last. Rong Tian (UW: University of Washington)H-Index: 44
view all 6 authors...
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...
135 CitationsSource
Cited By20
In summary, mitochondria are key to the cellular response to energetic demand, but are also vital to ROS signaling, calcium hemostasis, and regulation of apoptosis and necrosis pathways in cell death. Mitochondrial dysfunction and disruption of any of these vital processes can lead to chronic or acute pathology, particularly in tissues with high metabolic demand and mitochondrial content, such as the heart. In cardiac surgery, several perioperative factors can impact mitochondrial function, incl...
1 CitationsSource
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 ...
1 CitationsSource
#1Qianwen Chu (STU: Shantou University)
#2Yanmei Zhang (STU: Shantou University)H-Index: 17
Last. Ganggang Shi (STU: Shantou University)H-Index: 14
view all 11 authors...
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...
#1Jing Yang (UAB: University of Alabama at Birmingham)H-Index: 2
#2Jin He (UAB: University of Alabama at Birmingham)
Last. Min Xie (UAB: University of Alabama at Birmingham)H-Index: 1
view all 13 authors...
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 ...
#1Maria N. Sanz (University of Bern)H-Index: 1
#2Emilie Farine (University of Bern)H-Index: 2
Last. Sarah L. Longnus (University of Bern)H-Index: 6
view all 13 authors...
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 ...
#1Ge Zhang (Tianjin Medical University)H-Index: 2
#2Mingwei Sheng (Tianjin Medical University)H-Index: 2
Last. Zhelong Xu (Tianjin Medical University)H-Index: 6
view all 7 authors...
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...
6 CitationsSource
#1Yundan PanH-Index: 5
#2Na WangH-Index: 2
Last. Zhi YeH-Index: 1
view all 6 authors...
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...
9 CitationsSource
#1Qun Chen (VCU: Virginia Commonwealth University)H-Index: 30
#2Fadi N. Salloum (MCV: VCU Medical Center)H-Index: 43
#1Yanbin Su (JLU: Jilin University)H-Index: 1
#2Yanwen Su (JLU: Jilin University)H-Index: 2
Last. Shuxin Li (JLU: Jilin University)H-Index: 1
view all 8 authors...
ABSTRACTEvidences 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 d...
1 CitationsSource
#1André F. Ferreira (UC: University of Coimbra)H-Index: 7
#2Teresa Cunha-Oliveira (UC: University of Coimbra)H-Index: 17
Last. Paulo J. Oliveira (UC: University of Coimbra)H-Index: 52
view all 8 authors...
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 ...
6 CitationsSource