Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase γ

Lewis, William; Day, Brian J.; Kohler, James J.; Hosseini, Seyed Hamzeh; Chan, Sherine S.L.; Green, Elgin C; Haase, Chad P; Keebaugh, Erin S.; Long, Robert C.; Ludaway, Tomika; Russ, Rodney; Steltzer, Jeffrey; Tioleco, Nina; Santoianni, Robert; Copeland, William C.

doi:10.1038/labinvest.3700523

Cited by 118 publications

(115 citation statements)

References 51 publications

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“…All transgenic lines studied had decreased lifespans compared with the wild-type mice. Furthermore, the mutant mice developed cardiomegaly and mitochondrial DNA depletion, which are consistent with symptoms of congestive heart failure [Lewis et al, 2007]. This mouse model established that defective replication of mitochondrial DNA results in depletion of mitochondrial DNA and can subsequently cause cardiac dysfunction.…”

Section: Dna Polymerase Gamma (Pol C)supporting

confidence: 57%

“…Lewis et al developed a mouse in which the Y955C variant of Pol g [Lewis et al, 2007]. In humans, Y955C Pol g is the most common and severe autosomal dominant mutation in POLG that is also associated with the mitochondrial diseases of chronic progressive external opthalmoplegia (CPEO), Parkinsonism, and premature ovarian failure [Copeland, 2012].…”

Section: Dna Polymerase Gamma (Pol C)mentioning

confidence: 99%

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Mouse models of DNA polymerases

Menezes¹,

Sweasy²

2012

Environ and Mol Mutagen

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In 1956, Arthur Kornberg discovered the mechanism of the biological synthesis of DNA and was awarded the Nobel Prize in Physiology or Medicine in 1959 for this contribution, which included the isolation and characterization of Escherichia coli DNA polymerase I. Now there are 15 known DNA polymerases in mammalian cells that belong to four different families. These DNA polymerases function in many different cellular processes including DNA replication, DNA repair, and damage tolerance. Several biochemical and cell biological studies have provoked a further investigation of DNA polymerase function using mouse models in which polymerase genes have been altered using gene-targeting techniques. The phenotypes of mice harboring mutant alleles reveal the prominent role of DNA polymerases in embryogenesis, prevention of premature aging, and cancer suppression. Environ. Mol. Mutagen. 53:645-665, 2012. V V C 2012 Wiley Periodicals, Inc.

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Section: Dna Polymerase Gamma (Pol C)supporting

confidence: 57%

Section: Dna Polymerase Gamma (Pol C)mentioning

confidence: 99%

Mouse models of DNA polymerases

Menezes¹,

Sweasy²

2012

Environ and Mol Mutagen

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“…Myocardial samples (approximately 1 mm cubes) were cut, rapidly fixed in diluted Karnovsky's fixative, and processed. 2,25,26 Thin sections (0.5 m) were cut with a glass knife and stained with toluidine blue for orientation. Ultra thin (900 Å ) sections were cut with a diamond knife, stained with uranyl acetate and lead citrate and viewed on a Philips Morgagni electron microscope (Philips, Amsterdam, The Netherlands).…”

Section: Ultrastructural Pathological Evaluations (Electro Microscopymentioning

confidence: 99%

“…Each EM image was reviewed by two investigators for structural abnormalities (eg, intramitochondrial lamellar bodies, cristae reduplication). 2,25,26 Experimental Analysis and Statistics Values for LV Mass, LVEDD, mitochondrial H 2 O 2 and aconitase were compared in WT, TGs and AZT-treated cohorts using ANOVA in GraphPad Prism 4 (GraphPad, San Diego, CA, USA). Post-hoc testing used Newman-Keul's and unpaired t-test.…”

Section: Ultrastructural Pathological Evaluations (Electro Microscopymentioning

confidence: 99%

Transgenic mitochondrial superoxide dismutase and mitochondrially targeted catalase prevent antiretroviral-induced oxidative stress and cardiomyopathy

Kohler

Cucoranu

Fields

et al. 2009

Laboratory Investigation

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Transgenic mice (TG) were used to define mitochondrial oxidative stress and cardiomyopathy (CM) induced by zidovudine (AZT), an antiretroviral used to treat HIV/AIDS. Genetically engineered mice either depleted or overexpressed mitochondrial superoxide dismutase (SOD2 þ /À KOs and SOD2-OX, respectively) or expressed mitochondrially targeted catalase (mCAT). TGs and wild-type (WT) littermates were treated (oral AZT, 35 days). Cardiac mitochondrial H 2 O 2 , aconitase activity, histology and ultrastructure were analyzed. Left ventricle (LV) mass and LV end-diastolic dimension were determined echocardiographically. AZT induced cardiac oxidative stress and LV dysfunction in WTs. Cardiac mitochondrial H 2 O 2 increased and aconitase was inactivated in SOD2 þ /À KOs, and cardiac dysfunction was worsened by AZT. Conversely, the cardiac function in SOD2-OX and mCAT hearts was protected. In SOD2-OX and mCAT TG hearts, mitochondrial H 2 O 2 , LV mass and LV cavity volume resembled corresponding values from vehicle-treated WTs. AZT worsens cardiac dysfunction and increases mitochondrial H 2 O 2 in SOD2 þ /À KO. Conversely, both SOD2-OX and mCAT TGs prevent or attenuate AZT-induced cardiac oxidative stress and LV dysfunction. As dysfunctional changes are ameliorated by decreasing and worsened by increasing H 2 O 2 abundance, oxidative stress from H 2 O 2 is crucial pathogenetically in AZT-induced mitochondrial CM.

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“…A homozygous knock-in mouse expressing a proofreading-deficient version of PolgA (D257A mice), the nucleus-encoded catalytic subunit of mtDNA polymerase, has been generated to study mitochondrial disorders [65,178,179]. The knock-in mice develop a mtDNA mutator phenotype with an increase in the levels of point mutations, as well as increased amounts of deleted mtDNA.…”

Section: Models Of Hereditary Ataxiasmentioning

confidence: 99%

Animal Models of Human Cerebellar Ataxias: a Cornerstone for the Therapies of the Twenty-First Century

Manto

Marmolino

2009

Cerebellum

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Cerebellar ataxias represent a group of disabling neurological disorders. Our understanding of the pathogenesis of cerebellar ataxias is continuously expanding. A considerable number of laboratory animals with neurological mutations have been reported and numerous relevant animal models mimicking the phenotype of cerebellar ataxias are becoming available. These models greatly help dissecting the numerous mechanisms of cerebellar dysfunction, a major step for the assessment of therapeutics targeting a given deleterious pathway and for the screening of old or newly synthesized chemical compounds. Nevertheless, differences between animal models and human disorders should not be overlooked and difficulties in terms of characterization should not be occulted. The identification of the mutations of many hereditary ataxias, the development of valuable animal models, and the recent identifications of the molecular mechanisms underlying cerebellar disorders represent a combination of key factors for the development of anti-ataxic innovative therapies. It is anticipated that the twenty-first century will be the century of effective therapies in the field of cerebellar ataxias. The animal models are a cornerstone to reach this goal.

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Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase γ

Cited by 118 publications

References 51 publications

Mouse models of DNA polymerases

Mouse models of DNA polymerases

Transgenic mitochondrial superoxide dismutase and mitochondrially targeted catalase prevent antiretroviral-induced oxidative stress and cardiomyopathy

Animal Models of Human Cerebellar Ataxias: a Cornerstone for the Therapies of the Twenty-First Century

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