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

ABSTRACT: 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.

SUBMITTER: Pohjoismaki JL

PROVIDER: S-EPMC3845095 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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

Pohjoismäki Jaakko L O JL Williams Siôn L SL Boettger Thomas T Goffart Steffi S Kim Johnny J Suomalainen Anu A Moraes Carlos T CT Braun Thomas T

Proceedings of the National Academy of Sciences of the United States of America 20131111 48

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 b ...[more]

PMID: 24218554

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Project description:RATIONALE:Although mitochondrial diseases often cause abnormal myocardial development, the mechanisms by which mitochondria influence heart growth and function are poorly understood. OBJECTIVE:To investigate these disease mechanisms, we studied a genetic model of mitochondrial dysfunction caused by inactivation of Tfam (transcription factor A, mitochondrial), a nuclear-encoded gene that is essential for mitochondrial gene transcription and mitochondrial DNA replication. METHODS AND RESULTS:Tfam inactivation by Nkx2.5Cre caused mitochondrial dysfunction and embryonic lethal myocardial hypoplasia. Tfam inactivation was accompanied by elevated production of reactive oxygen species (ROS) and reduced cardiomyocyte proliferation. Mosaic embryonic Tfam inactivation confirmed that the block to cardiomyocyte proliferation was cell autonomous. Transcriptional profiling by RNA-seq demonstrated the activation of the DNA damage pathway. Pharmacological inhibition of ROS or the DNA damage response pathway restored cardiomyocyte proliferation in cultured fetal cardiomyocytes. Neonatal Tfam inactivation by AAV9-cTnT-Cre caused progressive, lethal dilated cardiomyopathy. Remarkably, postnatal Tfam inactivation and disruption of mitochondrial function did not impair cardiomyocyte maturation. Rather, it elevated ROS production, activated the DNA damage response pathway, and decreased cardiomyocyte proliferation. We identified a transient window during the first postnatal week when inhibition of ROS or the DNA damage response pathway ameliorated the detrimental effect of Tfam inactivation. CONCLUSIONS:Mitochondrial dysfunction caused by Tfam inactivation induced ROS production, activated the DNA damage response, and caused cardiomyocyte cell cycle arrest, ultimately resulting in lethal cardiomyopathy. Normal mitochondrial function was not required for cardiomyocyte maturation. Pharmacological inhibition of ROS or DNA damage response pathways is a potential strategy to prevent cardiac dysfunction caused by some forms of mitochondrial dysfunction.

Project description:BackgroundCellulose nanofibrils (CNFs) have emerged as a sustainable and environmentally friendly option for a broad range of applications. The fibrous nature and high biopersistence of CNFs call for a thorough toxicity assessment, but it is presently unclear which physico-chemical properties could play a role in determining the potential toxic response to CNF. Here, we assessed whether surface composition and size could modulate the genotoxicity of CNFs in human bronchial epithelial BEAS-2B cells. We examined three size fractions (fine, medium and coarse) of four CNFs with different surface chemistry: unmodified (U-CNF) and functionalized with 2,2,6,6-tetramethyl-piperidin-1-oxyl (TEMPO) (T-CNF), carboxymethyl (C-CNF) and epoxypropyltrimethylammonium chloride (EPTMAC) (E-CNF). In addition, the source fibre was also evaluated as a non-nanosized material.ResultsThe presence of the surface charged groups in the functionalized CNF samples resulted in higher amounts of individual nanofibrils and less aggregation compared with the U-CNF. T-CNF was the most homogenous, in agreement with its high surface group density. However, the colloidal stability of all the CNF samples dropped when dispersed in cell culture medium, especially in the case of T-CNF. CNF was internalized by a minority of BEAS-2B cells. No remarkable cytotoxic effects were induced by any of the cellulosic materials. All cellulosic materials, except the medium fraction of U-CNF, induced a dose-dependent intracellular formation of reactive oxygen species (ROS). The fine fraction of E-CNF, which induced DNA damage (measured by the comet assay) and chromosome damage (measured by the micronucleus assay), and the coarse fraction of C-CNF, which produced chromosome damage, also showed the most effective induction of ROS in their respective size fractions.ConclusionsSurface chemistry and size modulate the in vitro intracellular ROS formation and the induction of genotoxic effects by fibrillated celluloses. One cationic (fine E-CNF) and one anionic (coarse C-CNF) CNF showed primary genotoxic effects, possibly partly through ROS generation. However, the conclusions cannot be generalized to all types of CNFs, as the synthesis process and the dispersion method used for testing affect their physico-chemical properties and, hence, their toxic effects.

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

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

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