Multiple deficiencies in antioxidant enzymes in mice result in a compound increase in sensitivity to oxidative stress

Remmen, Holly Van; Qi, Wenbo; Sabia, Marian; Freeman, Gregory L.; Estlack, Larry E.; Hong, Yun–Chul; Guo, ZhongMao; Huang, Ting; Strong, Randy; Lee, Shuko; Epstein, Charles J.; Richardson, Arlan

doi:10.1016/j.freeradbiomed.2004.03.016

Cited by 115 publications

(65 citation statements)

References 33 publications

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“…The implicated link between mtDNA integrity and apoptotic signaling might also explain the increased rate of apoptosis in PolG mutator mice, which show high levels of linear mtDNA deletions without increased ROS production (36,37). Sod2 +/− cardiomyocytes are more sensitive to apoptosis caused by cellular stress during myocardial infarction (38) or other adverse conditions (8,39), although it is difficult to score a measurable increase of apoptotic cardiomyocytes because of the gradual development of the age-dependent cardiomyopathy in Sod2 +/− mice. Furthermore, aged Tw + mouse hearts accumulate cytochrome oxidase negative cardiomyocytes (Fig.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Twinkle-helicase protects cardiomyocytes from genotoxic stress caused by reactive oxygen species

Pohjoismäki

Williams

Boettger

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Mitochondrial DNA (mtDNA) in adult human heart is characterized by complex molecular forms held together by junctional molecules of unknown biological significance. These junctions are not present in mouse hearts and emerge in humans during postnatal development, concomitant with increased demand for oxidative metabolism. To analyze the role of mtDNA organization during oxidative stress in cardiomyocytes, we used a mouse model, which recapitulates the complex mtDNA organization of human hearts by overexpression of the mitochondrial helicase, TWINKLE. Overexpression of TWINKLE rescued the oxidative damage induced replication stalling of mtDNA, reduced mtDNA point mutation load, and modified mtDNA rearrangements in heterozygous mitochondrial superoxide dismutase knockout hearts, as well as ameliorated cardiomyopathy in mice superoxide dismutase knockout in a p21-dependent manner. We conclude that mtDNA integrity influences cell survival and reason that tissue specific modes of mtDNA maintenance represent an adaptation to oxidative stress.recombination | mtDNA mutations | repair

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Section: Discussionmentioning

confidence: 99%

Overexpression of Twinkle-helicase protects cardiomyocytes from genotoxic stress caused by reactive oxygen species

Pohjoismäki

Williams

Boettger

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Redox cycling is a primary cause of PQ-induced toxicity as evidenced by protection from adverse PQ effects by overexpression of superoxide dismutase (SOD) (108) or via administration of SOD mimetics (68). Conversely, deficiency in antioxidant enzymes causes hypersensitivity to PQ treatment in vivo (112). In vitro in SH-SY5Y cells, PQ has been shown to increase generation of ROS and to concomitantly decrease antioxidants (117).…”

Section: Paraquat Metabolism and Mitochondrial Mechanisms Of Neurotoxmentioning

confidence: 99%

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

Martinez

Greenamyre

2012

Antioxidants & Redox Signaling

228

155

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Significance: Parkinson's disease (PD) is a neurodegenerative disorder characterized, in part, by the progressive and selective loss of dopaminergic neuron cell bodies within the substantia nigra pars compacta (SNpc) and the associated deficiency of the neurotransmitter dopamine (DA) in the striatum, which gives rise to the typical motor symptoms of PD. The mechanisms that contribute to the induction and progressive cell death of dopaminergic neurons in PD are multi-faceted and remain incompletely understood. Data from epidemiological studies in humans and molecular studies in genetic, as well as toxin-induced animal models of parkinsonism, indicate that mitochondrial dysfunction occurs early in the pathogenesis of both familial and idiopathic PD. In this review, we provide an overview of toxin models of mitochondrial dysfunction in experimental Parkinson's disease and discuss mitochondrial mechanisms of neurotoxicity. Recent Advances: A new toxin model using the mitochondrial toxin trichloroethylene was recently described and novel methods, such as intranasal exposure to toxins, have been explored. Additionally, recent research conducted in toxin models of parkinsonism provides an emerging emphasis on extranigral aspects of PD pathology. Critical Issues: Unfortunately, none of the existing animal models of experimental PD completely mimics the etiology, progression, and pathology of human PD. Future Directions: Continued efforts to optimize established animal models of parkinsonism, as well as the development and characterization of new animal models are essential, as there still remains a disconnect in terms of translating mechanistic observations in animal models of experimental PD into bona fide diseasemodifying therapeutics for human PD patients. Antioxid. Redox Signal. 16, 920-934.

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“…Modification of these antioxidant enzymes resulting from the knockout of manganese superoxide dismutase or glutathione peroxidase genes can significantly affect mitochondrial activity and ROS production and has been linked to hypertension and salt sensitivity in mice. [12][13][14][15] The precise contribution of mitochondria to the total ROS production in the vessel wall or other cardiovascular tissues …”

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confidence: 99%

Mitochondria-Targeted Antioxidant MitoQ ₁₀ Improves Endothelial Function and Attenuates Cardiac Hypertrophy

et al. 2009

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Abstract-Mitochondria are a major site of reactive oxygen species production, which may contribute to the development of cardiovascular disease. Protecting mitochondria from oxidative damage should be an effective therapeutic strategy; however, conventional antioxidants are ineffective, because they cannot penetrate the mitochondria. This study investigated the role of mitochondrial oxidative stress during development of hypertension in the stroke-prone spontaneously hypertensive rat, using the mitochondria-targeted antioxidant, MitoQ 10 . Eight-week-old male strokeprone spontaneously hypertensive rats were treated with MitoQ 10 (500 mol/L; nϭ16), control compound decyltriphenylphosphonium (decylTPP; 500 mol/L; nϭ8), or vehicle (nϭ9) in drinking water for 8 weeks. Ϫ goes on to produce a range of damaging ROS that lead to nonspecific modification of mitochondrial proteins, lipids, and nucleic acids, thereby altering mitochondrial function. 3-5 Mitochondrial DNA is particularly susceptible to modification by ROS, and this damage can rapidly lead to functional changes in the cell, because it encodes 13 essential polypeptide components of the mitochondrial respiratory chain. 4 Extensive evidence suggests that mitochondrial DNA damage occurs in cardiovascular disease in humans, animal models, and cellular models. 3,[7][8][9] Mitochondria are normally protected from oxidative damage by a multilayer network of mitochondrial antioxidant systems. 10,11 These include the mitochondrial matrix enzyme manganese superoxide dismutase, which converts the O 2 Ϫ anion to hydrogen peroxide, glutathione peroxidase, and peroxiredoxins 3 and 5, which readily convert hydrogen peroxide to water 7,10 and ultimately prevent forms of mitochondrial oxidative damage, eg, lipid peroxidation. Modification of these antioxidant enzymes resulting from the knockout of manganese superoxide dismutase or glutathione peroxidase genes can significantly affect mitochondrial activity and ROS production and has been linked to hypertension and salt sensitivity in mice. [12][13][14][15] The precise contribution of mitochondria to the total ROS production in the vessel wall or other cardiovascular tissues

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Multiple deficiencies in antioxidant enzymes in mice result in a compound increase in sensitivity to oxidative stress

Cited by 115 publications

References 33 publications

Overexpression of Twinkle-helicase protects cardiomyocytes from genotoxic stress caused by reactive oxygen species

Overexpression of Twinkle-helicase protects cardiomyocytes from genotoxic stress caused by reactive oxygen species

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

Mitochondria-Targeted Antioxidant MitoQ ₁₀ Improves Endothelial Function and Attenuates Cardiac Hypertrophy

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Multiple deficiencies in antioxidant enzymes in mice result in a compound increase in sensitivity to oxidative stress

Cited by 115 publications

References 33 publications

Overexpression of Twinkle-helicase protects cardiomyocytes from genotoxic stress caused by reactive oxygen species

Overexpression of Twinkle-helicase protects cardiomyocytes from genotoxic stress caused by reactive oxygen species

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

Mitochondria-Targeted Antioxidant MitoQ 10 Improves Endothelial Function and Attenuates Cardiac Hypertrophy

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Product

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Mitochondria-Targeted Antioxidant MitoQ ₁₀ Improves Endothelial Function and Attenuates Cardiac Hypertrophy