BRCA2 deficiency reveals that oxidative stress impairs RNaseH1 function to cripple mitochondrial DNA maintenance

Introduction. Nonalcoholic fatty liver disease (NAFLD) is becoming more common around the world and it may progress to cirrhosis and liver failure, increasing mortality risk. In hemodialysis (HD) patients, NAFLD may be a novel risk factor for their high cardiovascular mortality. Heightened oxidative stress is highly prevalent in HD patients. However, the relationship between oxidative stress and NAFLD in HD patients is not well defined.Methods. We studied seventy-one stable nondiabetic HD patients. Nineteen patients had the diagnosis of NAFLD by ultrasonography. Blood levels of oxidative stress markers were measured in each patient, including thiobarbituric acid reactive substances (TBARS), free thiols, superoxide dismutase (SOD) activities, and glutathione peroxidase (GPx) activity. The copy numbers of mitochondrial DNA (mtDNA) in peripheral leukocytes were also determined. Demographic, biochemistry, and hemogram data were recorded. The two groups of patients were compared in order to determine the factors associated with NAFLD in HD patients.Findings. Compared to those without NAFLD, nondiabetic HD patients with NAFLD had significantly higher mtDNA copy number and GPx levels. The two groups did not differ significantly in dialysis adequacy, hemoglobin, serum calcium, phosphorus, albumin, liver function tests, or lipid profiles. Regression analysis confirmed mtDNA copy numbers and GPx levels as two independent factors associated with NAFLD. Compared to those with polysulfone, patients dialyzed with cellulose membrane have significantly higher levels of TBARS. However, patients with or without NAFLD did not differ in their use of either dialysis membrane.Discussion. Oxidative stress (represented by antioxidant defense, GPx) and mitochondrial DNA copy numbers are independently associated with fatty liver disease in nondiabetic HD patients. The diagnostic and therapeutic implications of this key observation warrant further exploration.

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Mitochondrial DNA Mutation, Oxidative Stress, and Alteration of Gene Expression in Human Aging

Oxidative Stress and Disease - Mitochondria in Health and Disease ◽

10.1201/9781420028843.ch6 ◽

2005 ◽

pp. 319-362 ◽

Cited By ~ 1

Author(s):

Hsin-Chen Lee ◽

Yau-Huei Wei

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Mitochondrial Dna ◽

Human Aging ◽

Mitochondrial Dna Mutation ◽

Dna Mutation

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Complete loss of mitofusins leads to gross respiratory chain dysfunction due to aberrant mitochondrial DNA maintenance and distribution

Biochimica et Biophysica Acta (BBA) - Bioenergetics ◽

10.1016/j.bbabio.2016.04.417 ◽

2016 ◽

Vol 1857 ◽

pp. e27

Author(s):

Eduardo Silva Ramos ◽

Elisa Motori ◽

Christian Brüser ◽

Inge Kühl ◽

Benedetta Ruzzenente ◽

...

Keyword(s):

Mitochondrial Dna ◽

Respiratory Chain ◽

Complete Loss ◽

Dna Maintenance

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Nicotinamide Riboside Inhibits Alcohol-Induced Inflammation and Oxidative Stress in Macrophages

Current Developments in Nutrition ◽

10.1093/cdn/nzaa045_043 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 410-410

Author(s):

Hyunju Kang ◽

Young-Ki Park ◽

Ji-Young Lee

Keyword(s):

Oxidative Stress ◽

Mitochondrial Dna ◽

Mitochondrial Respiration ◽

Nuclear Translocation ◽

Antioxidant Properties ◽

Sirtuin 1 ◽

Mouse Bone Marrow ◽

Nicotinamide Riboside ◽

Mitochondrial Dna Copy Number ◽

And Oxidative Stress

Abstract Objectives Macrophages play an essential role in the development of alcohol-induced inflammation. The objective of this study was to investigate whether nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD+) precursor naturally found in milk, can attenuate alcohol-induced inflammation and oxidative stress in macrophages with the elucidation of mechanisms of action. Methods RAW 264.7 macrophages and mouse bone marrow-derived macrophages (BMDMs) were stimulated with 80 mM ethanol with or without 1 mM of NR for 72 h. Expression of genes associated with inflammation and oxidative stress and cellular reactive oxygen species (ROS) accumulation were measured. Also, to evaluate the contribution of sirtuin 1 (SIRT1) to the NR's effect, cellular NAD + level (a cofactor of SIRT1), SIRT1 activity, and mitochondrial DNA copy number were measured. SIRT1 activity was inhibited or activated by sirtinol and resveratrol, respectively, to confirm SIRT1 functions further. Parameters related to mitochondrial respiration were determined using a Seahorse XFe24 Extracellular Flux analyzer. Results NR significantly decreased ethanol-induced inflammatory gene expression, with a concomitant decrease in nuclear translocation of nuclear factor kB p65 in macrophages. Increased cellular ROS levels by ethanol were also attenuated concomitantly with decreased expression of NADPH oxidase 2, a ROS-producing enzyme, by NR in both macrophage cell types. Ethanol decreased SIRT1 mRNA, protein and activity, cellular NAD + level, and mitochondrial DNA, all of which were markedly attenuated by NR. SIRT1 inhibition by sirtinol augmented the inflammatory effects of ethanol, while SIRT1 activation by resveratrol elicited the opposing results. Ethanol increased mitochondrial respiration, ATP production, and proton leak, but decreased maximal respiration and spare respiratory capacity. The ethanol-induced changes in mitochondrial respiration were abolished by NR. Conclusions NR showed anti-inflammatory and antioxidant properties in ethanol-treated macrophages by counteracting the effect of ethanol on lowering SIRT1 expression and cellular NAD+ levels. Therefore, NR may be a potential therapeutic agent for alcohol-induced inflammation and oxidative stress. Funding Sources This work is supported by the NIH 3R01DK108254-04S1.

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Exposure to environmental radionuclides alters mitochondrial DNA maintenance in a wild rodent

Evolutionary Ecology ◽

10.1007/s10682-019-10028-x ◽

2020 ◽

Vol 34 (2) ◽

pp. 163-174 ◽

Cited By ~ 1

Author(s):

Jenni Kesäniemi ◽

Anton Lavrinienko ◽

Eugene Tukalenko ◽

Ana Filipa Moutinho ◽

Tapio Mappes ◽

...

Keyword(s):

Mitochondrial Dna ◽

Wild Rodent ◽

Dna Maintenance ◽

Environmental Radionuclides

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A novel mtDNA repair fusion protein attenuates maladaptive remodeling and preserves cardiac function in heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00515.2017 ◽

2018 ◽

Vol 314 (2) ◽

pp. H311-H321 ◽

Cited By ~ 10

Author(s):

Jessica M. Bradley ◽

Zhen Li ◽

Chelsea L. Organ ◽

David J. Polhemus ◽

Hiroyuki Otsuka ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Mitochondrial Dna ◽

Myocardial Ischemia ◽

Fusion Protein ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Myocardial Infarct Size ◽

Endonuclease Iii ◽

Mtdna Repair

Oxidative stress results in mtDNA damage and contributes to myocardial cell death. mtDNA repair enzymes are crucial for mtDNA repair and cell survival. We investigated a novel, mitochondria-targeted fusion protein (Exscien1-III) containing endonuclease III in myocardial ischemia-reperfusion injury and transverse aortic constriction (TAC)-induced heart failure. Male C57/BL6J mice (10–12 wk) were subjected to 45 min of myocardial ischemia and either 24 h or 4 wk of reperfusion. Exscien1-III (4 mg/kg ip) or vehicle was administered at the time of reperfusion. Male C57/BL6J mice were subjected to TAC, and Exscien1-III (4 mg/kg i.p) or vehicle was administered daily starting at 3 wk post-TAC and continued for 12 wk. Echocardiography was performed to assess left ventricular (LV) structure and function. Exscien1-III reduced myocardial infarct size ( P < 0.01) at 24 h of reperfusion and preserved LV ejection fraction at 4 wk postmyocardial ischemia. Exscien1-III attenuated TAC-induced LV dilation and dysfunction at 6–12 wk post-TAC ( P < 0.05). Exscien1-III reduced ( P < 0.05) cardiac hypertrophy and maladaptive remodeling after TAC. Assessment of cardiac mitochondria showed that Exscien1-III localized to mitochondria and increased mitochondrial antioxidant and reduced apoptotic markers. In conclusion, our results indicate that administration of Exscien1-III provides significant protection against myocardial ischemia and preserves myocardial structure and LV performance in the setting of heart failure. NEW & NOTEWORTHY Oxidative stress-induced mitochondrial DNA damage is a prominent feature in the pathogenesis of cardiovascular diseases. In the present study, we demonstrate the efficacy of a novel, mitochondria-targeted fusion protein that traffics endonuclease III specifically for mitochondrial DNA repair in two well-characterized murine models of cardiac injury and failure.

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