O-GlcNAcylation of 8-Oxoguanine DNA Glycosylase (Ogg1) Impairs Oxidative Mitochondrial DNA Lesion Repair in Diabetic Hearts

Cividini, Federico; Scott, Brian T.; Dai, Anzhi; Han, Wenlong; Suárez, Jorge; Díaz-Juárez, Julieta; Diemer, Tanja; Casteel, Darren E.; Dillmann, Wolfgang H.

doi:10.1074/jbc.m116.754481

Cited by 53 publications

(46 citation statements)

References 48 publications

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“…For example, hyperglycemia is conventionally associated with the over‐production of ROS. OGG1 was found highly O‐GlcNAcylated in diabetic mice compared with controls, and O‐GlcNAcylation inhibited OGG1 activity 54 . In light of the results of the present study, we may propose that O‐GlcNAcylated OGG1 affects the expression of those genes implicated in diabetic pathogenesis despite the impaired enzymatic activity.…”

Section: Discussionsupporting

confidence: 52%

Enzymatically inactive OGG1 binds to DNA and steers base excision repair toward gene transcription

et al. 2020

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8‐Oxoguanine DNA glycosylase1 (OGG1)‐initiated base excision repair (BER) is the primary pathway to remove the pre‐mutagenic 8‐oxo‐7,8‐dihydroguanine (8‐oxoG) from DNA. Recent studies documented 8‐oxoG serves as an epigenetic‐like mark and OGG1 modulates gene expression in oxidatively stressed cells. For this new role of OGG1, two distinct mechanisms have been proposed: one is coupled to base excision, while the other only requires substrate binding of OGG1––both resulting in conformational adjustment in the adjacent DNA sequences providing access for transcription factors to their cis‐elements. The present study aimed to examine if BER activity of OGG1 is required for pro‐inflammatory gene expression. To this end, Ogg1/OGG1 knockout/depleted cells were transfected with constructs expressing wild‐type (wt) and repair‐deficient mutants of OGG1. OGG1's promoter enrichment, oxidative state, and gene expression were examined. Results showed that TNFα exposure increased levels of oxidatively modified cysteine(s) of wt OGG1 without impairing its association with promoter and facilitated gene expression. The excision deficient K249Q mutant was even a more potent activator of gene expression; whereas, mutant OGG1 with impaired substrate recognition/binding was not. These data suggested the interaction of OGG1 with its substrate at regulatory regions followed by conformational adjustment in the adjacent DNA is the primary mode to modulate inflammatory gene expression.

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Section: Discussionsupporting

confidence: 52%

Enzymatically inactive OGG1 binds to DNA and steers base excision repair toward gene transcription

et al. 2020

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“…Diabetes was induced in C57BL/6NHsd mice (25 g, 3 months old) by giving a daily intraperitoneal injection of STZ (40 mg/kg) for five consecutive days, as previously described (45). Diabetes onset was documented by measuring blood glucose above 250 mg/dl.…”

Section: Diabetic Mouse Modelmentioning

confidence: 99%

“…Mitochondria were isolated as previously described (45). To ensure mitochondrial viability for ATP production and O 2 consumption assays all steps were performed at 4°C.…”

Section: Mitochondria Preparationmentioning

confidence: 99%

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Restoring mitochondrial calcium uniporter expression in diabetic mouse heart improves mitochondrial calcium handling and cardiac function

Suárez

Cividini

Scott

et al. 2018

Journal of Biological Chemistry

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Diabetes mellitus is a growing health care problem, resulting in significant cardiovascular morbidity and mortality. Diabetes also increases the risk for heart failure (HF) and decreased cardiac myocyte function, which are linked to changes in cardiac mitochondrial energy metabolism. The free mitochondrial calcium level ([Ca] ) is fundamental in activating the mitochondrial respiratory chain complexes and ATP production and is also known toregulate pyruvate dehydrogenase complex (PDC) activity. The mitochondrial calcium uniporter (MCU) complex (MCUC) plays a major role in mediating mitochondrial Ca import, and its expression and function therefore have a marked impact on cardiac myocyte metabolism and function. Here, we investigated MCU's role in mitochondrial Ca handling, mitochondrial function, glucose oxidation, and cardiac function in the heart of diabetic mice. We found that diabetic mouse hearts exhibit altered expression of MCU and MCUC members and a resulting decrease in [Ca] , mitochondrial Ca uptake, mitochondrial energetic function, and cardiac function. Adeno-associated virus-based normalization of MCU levels in these hearts restored mitochondrial Ca handling, reduced PDC phosphorylation levels, and increased PDC activity. These changes were associated with cardiac metabolic reprogramming toward normal physiological glucose oxidation. This reprogramming likely contributed to the restoration of both cardiac myocyte and heart function to nondiabetic levels without any observed detrimental effects. These findings support the hypothesis that abnormal mitochondrial Ca handling and its negative consequences can be ameliorated in diabetes by restoring MCU levels via adeno-associated virus-based MCU transgene expression.

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“…Under diabetic conditions, oxidative damage to the mtDNA may be an important consequence of excess ROS production [11], inducing a loss of mitochondrial networks, decreased expression of mitochondrial respiratory complexes, and consequent T2DM-related atherosclerosis [12][13][14]. Among numerous types of mtDNA oxidative lesions, the formation of 8-hydroxy-2′deoxyguanosine is the most abundant one, reflecting a steady-state level of oxidative damage occurring within mtDNA [15]. In kidney of diabetic rats, levels of 8-OHdG were up-regulated in mtDNA but not in nuclear DNA [16].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial 8-hydroxy-2′-deoxyguanosine and coronary artery disease in patients with type 2 diabetes mellitus

Wang

Cui

Liu

et al. 2020

Cardiovasc Diabetol

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Background: Little is known about whether mitochondria 8-hydroxy-2′-deoxyguanosine (8-OHdG), a biomarker of mitochondrial DNA (mtDNA) oxidative damage, contributes to the development of coronary artery disease (CAD) in diabetic patients. Here, we explored the associations of mtDNA 8-OHdG in leukocytes with obstructive CAD, coronary stenosis severity, cardiovascular biomarkers, and 1-year adverse outcomes after coronary revascularization in patients with type 2 diabetes mellitus (T2DM). Methods: In a total of 1920 consecutive patients with T2DM who underwent coronary angiography due to symptoms of angina or angina equivalents, the presence of obstructive CAD, the number of diseased vessels with ≥ 50% stenosis, and modified Gensini score were cross-sectionally evaluated; the level of mtDNA 8-OHdG was quantified by quantitative PCR. Then, 701 of 1920 diabetic patients who further received coronary revascularization completed 1-year prospective follow-up to document major adverse cardiovascular and cerebral events (MACCEs). In vitro experiments were also performed to observe the effects of mtDNA oxidative damage in high glucose-cultured human umbilical vein endothelial cells (HUVECs). Results: Cross-sectionally, greater mtDNA 8-OHdG was associated with increased odds of obstructive CAD (odds ratio [OR] 1.38, 95% CI confidence interval 1.24-1.52), higher degree of coronary stenosis (number of diseased vessels: OR 1.29, 95% CI 1.19-1.41; modified Gensini scores: OR 1.28, 95% CI 1.18-1.39), and higher levels of C-reactive protein (β 0.18, 95% CI 0.06-0.31) after adjusting for confounders. Sensitivity analyses using propensity score matching yielded similar results. Stratification by smoking status showed that the association between mtDNA 8-OHdG and obstructive CAD was most evident in current smokers (P interation < 0.01). Prospectively, the adjusted hazards ratio per 1-SD increase in mtDNA 8-OHdG was 1.59 (95% CI 1.33-1.90) for predicting 1-year MACCEs after revascularization. In HUVECs, exposure to antimycin A, an inducer for mtDNA oxidative damage, led to adverse alterations in markers of mitochondrial and endothelia function. Conclusion: Greater mtDNA 8-OHdG in leukocytes may serve as an independent risk factor for CAD in patients with T2DM.

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O-GlcNAcylation of 8-Oxoguanine DNA Glycosylase (Ogg1) Impairs Oxidative Mitochondrial DNA Lesion Repair in Diabetic Hearts

Cited by 53 publications

References 48 publications

Enzymatically inactive OGG1 binds to DNA and steers base excision repair toward gene transcription

Enzymatically inactive OGG1 binds to DNA and steers base excision repair toward gene transcription

Restoring mitochondrial calcium uniporter expression in diabetic mouse heart improves mitochondrial calcium handling and cardiac function

Mitochondrial 8-hydroxy-2′-deoxyguanosine and coronary artery disease in patients with type 2 diabetes mellitus

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