Mitochondrial impairment is accompanied by impaired oxidative DNA repair in the nucleus

Delsite, Robert

doi:10.1093/mutage/geg027

Cited by 63 publications

(58 citation statements)

References 44 publications

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“…In addition to deletions, it is possible that a reduction in the copy number of mtDNA could alter mitochondrial function, which may also lead to increased cellular ROS. Interestingly, impairment of DNA repair and increased oxidative damage to the nuclear genome have been reported in cells depleted of mtDNA (17,18). Furthermore, we have previously shown an increase in background nuclear mutations in mtDNA-depleted (U0) cells (5).…”

Section: Introductionmentioning

confidence: 78%

Arsenic Induced Mitochondrial DNA Damage and Altered Mitochondrial Oxidative Function: Implications for Genotoxic Mechanisms in Mammalian Cells

Partridge¹,

Huang

Hernandez-Rosa

et al. 2007

Cancer Research

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Arsenic is a well-established human carcinogen that is chronically consumed in drinking water by millions of people worldwide. Recent evidence has suggested that arsenic is a genotoxic carcinogen. Furthermore, we have shown that mitochondria mediate the mutagenic effects of arsenic in mammalian cells, as arsenic did not induce nuclear mutations in mitochondrial DNA (mtDNA)-depleted cells. Using the human-hamster hybrid A L cells, we show here that arsenic alters mitochondrial function by decreasing cytochrome c oxidase function and oxygen consumption but increasing citrate synthase function. These alterations correlated with depletion in mtDNA copy number and increase in large heteroplasmic mtDNA deletions. In addition, mtDNA isolated periodically from cultures treated continuously with arsenic did not consistently display the same deletion pattern, indicating that the mitochondrial genome was subjected to repeated and continuous damage. These data support the theory that the mitochondria, and particularly mtDNA, are important targets of the mutagenic effects of arsenic in mammalian cells. [Cancer Res 2007;67(11):5239-47]

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Section: Introductionmentioning

confidence: 78%

Arsenic Induced Mitochondrial DNA Damage and Altered Mitochondrial Oxidative Function: Implications for Genotoxic Mechanisms in Mammalian Cells

Partridge¹,

Huang

Hernandez-Rosa

et al. 2007

Cancer Research

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“…Measurement of intracellular ROS production was made using superoxide sensitive probe dihydroethidium (DHE) as described. 15 Briefly, cells were collected by trypsinization and washed twice with HBSS with 0.5 % FBS. Cells were suspended in 1 ml of washing buffer and loaded with dye DHE (10 µM) for 30 min at 37˚C.…”

Section: Methodsmentioning

confidence: 99%

Cross talk between mitochondria and superoxide generating NADPH oxidase in breast and ovarian tumors

Desouki¹,

Kulawiec²,

Bansal³

et al. 2005

Cancer Biology & Therapy

154

164

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Reactive oxygen species (ROS) function as cellular switches for signaling cascade involved in cell growth, cell death, mitogenesis, angiogenesis and carcinogenesis. ROS are produced as a byproduct of oxidative phosphorylation (OXPHOS) in the mitochondria. It is estimated that 2-4% of the oxygen consumed during OXPHOS is converted to ROS. Besides mitochondria, NADPH-oxidase 1 (Nox1) also generates a significant amount of ROS in the cell. In this paper, we tested the hypothesis that mitochondria control Nox 1 redox signaling and the loss of control of this signaling contribute to tumorigenesis. We analyzed Nox1 expression in a mitochondrial gene knockout (ρ 0 ) cell line and in the isogenic cybrid cell line in which mitochondrial genes were restored by transfer of wild type mitochondria into ρ 0 cells. Our study revealed, for the first time, that the inactivation of mitochondrial genes leads to down-regulation of Nox1 and that the transfer of wild type mitochondrial genes restored the Nox1 expression to a level comparable to that in the parental cell line. Consistent with Nox1 down-regulation, we found that ρ 0 cells contained low levels of superoxide anion and that superoxide levels reversed to parental levels in cybrid cells when Nox1 expression was restored by transfer of wild type mitochondria. Increasing mitochondrial superoxide levels also increased the expression of Nox1 in parental cells. Confocal microscopy studies revealed that Nox1 localizes in the mitochondria. Nox1 was highly expressed in breast (86%) and ovarian (71%) tumors and that its expression positively correlated with expression of cytochrome C oxidase encoded by mtDNA. Our study, described in this paper demonstrates the existence of cross talk between the mitochondria and NADPH oxidase. Furthermore, our studies suggest that mitochondria control Nox1 redox signaling and the loss of control of this signaling contributes to breast and ovarian tumorigenesis.

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“…Since all the other proteins tested can be located in the mitochondrial membrane, it is tempting to speculate that overexpression of Bcl-2 family members affects mitochondria membranes resulting in mitochondrial signaling reminiscent of the 'retrograde response' (Butow and Avadhani, 2004), affecting in fine HR. In line with this, depletion of mitochondrial DNA compromises the respiratory chain function, affects the mitochondrial membrane and results in mutagenesis of nuclear DNA (Delsite et al, 2003). In the particular case of Bid protein, it has been shown to exhibit a nuclear localization, to be phosphorylated by ATM and required for the ATM-dependent cell cycle checkpoint (Zinkel et al, 2005); it could thus affect the ATMdependent regulation of HR.…”

Section: Inhibition Of Homologous Recombination By Bax or Bidmentioning

confidence: 95%

Bax and Bid, two proapoptotic Bcl-2 family members, inhibit homologous recombination, independently of apoptosis regulation

et al. 2006

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In order to analyse the relationships between regulation of apoptosis and homologous recombination (HR), we overexpressed proapoptotic Bax or only-BH3 Bid proteins or antiapoptotic Bcl-2 or Bcl-XL, in hamster CHO cells or in SV40-transformed human fibroblasts. We measured HR induced by c-rays, UVC or a specific double-strand cleavage targeted in the recombination substrate by the meganuclease I-SceI. We show here that the induction of both recombinant cells and recombinant colonies was impaired when expressing Bcl-2 family members, in hamster as well as in human cells. Moreover, the pro-as well as antiapoptotic Bcl-2 family members inhibited HR, independently of degradation of the RAD51 recombination protein and of their impact on apoptosis. These data reveal a mechanism of HR downregulation by potentially proapoptotic proteins, distinct from and parallel to degradation of recombination proteins, a situation that should also optimize the efficiency of programmed cell death.

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Mitochondrial impairment is accompanied by impaired oxidative DNA repair in the nucleus

Cited by 63 publications

References 44 publications

Arsenic Induced Mitochondrial DNA Damage and Altered Mitochondrial Oxidative Function: Implications for Genotoxic Mechanisms in Mammalian Cells

Arsenic Induced Mitochondrial DNA Damage and Altered Mitochondrial Oxidative Function: Implications for Genotoxic Mechanisms in Mammalian Cells

Cross talk between mitochondria and superoxide generating NADPH oxidase in breast and ovarian tumors

Bax and Bid, two proapoptotic Bcl-2 family members, inhibit homologous recombination, independently of apoptosis regulation

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