Desferrioxamine treatment increases the genomic stability of Ataxia-telangiectasia cells

Shackelford, Rodney E.; Manuszak, Ryan P.; Johnson, Cybele D.; Hellrung, Daniel J.; Steele, Timothy A.; Link, Charles J.; Wang, Suming

doi:10.1016/s1568-7864(03)00090-9

Cited by 22 publications

(8 citation statements)

References 23 publications

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“…7, which is published as supporting information on the PNAS web site). The enhancement of CREB binding to the mitochondrial genome by DFO may increase mitochondrial genome stability and maintain normal mitochondrial respiratory protein expression and membrane potential to abrogate cellular oxidative stress in neurons (44). Our finding that PKA and CREB localize in the mitochondria and are regulated by the antioxidant DFO raises the possibility that neuronal survival may additionally be affected by the regulation of mitochondrial function through the PKA and CREB signaling pathways.…”

Section: Discussionmentioning

confidence: 80%

Antioxidants modulate mitochondrial PKA and increase CREB binding to D-loop DNA of the mitochondrial genome in neurons

Ryu

Lee

Impey³

et al. 2005

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

146

128

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The protein kinase A (PKA) and the cAMP response element (CRE) binding protein (CREB) signaling pathways mediate plasticity and prosurvival responses in neurons through their ability to regulate gene expression. The PKA-CREB signaling mechanism has been well characterized in terms of nuclear gene expression. We show that the PKA catalytic and regulatory subunits and CREB are localized to the mitochondrial matrix of neurons. Mitochondrial CRE sites were identified by using both serial analyses of chromatin occupancy and chromatin immunoprecipitation. Deferoxamine (DFO), an antioxidant and iron chelator known to inhibit oxidative stress-induced death, activated mitochondrial PKA and increased mitochondrial CREB phosphorylation (Ser-133). DFO increased CREB binding to CRE in the mitochondrial D-loop DNA and D-loop CRE-driven luciferase activity. In contrast, KT5720, a specific inhibitor of PKA, reduced DFO-mediated neuronal survival against oxidative stress induced by glutathione depletion. Neuronal survival by DFO may be, in part, mediated by the mitochondrial PKA-dependent pathway. These results suggest that the regulation of mitochondrial function via the mitochondrial PKA and CREB pathways may underlie some of the salutary effects of DFO in neurons. P rotein kinase A (PKA) and cAMP response element (CRE) binding protein (CREB) play important roles in neuronal plasticity by altering expression of target genes in response to environmental stimuli (1-3). The PKA and CREB pathway is involved in neuronal survival of the central and peripheral nervous systems (4, 5). PKA is a tetramer consisting of two regulatory (Reg) and two catalytic (Cat) subunits. The binding of cAMP to a Reg subunit dissociates the holoenzyme into two free Cat subunits, which induce the phosphorylation of cellular substrates and a Reg subunit dimer. PKA phosphorylates CREB at Ser-133. Phosphorylated CREB (pCREB) subsequently binds to CRE and recruits the CREB binding protein, a transcriptional coactivator, to activate gene expression (6-8). It has been shown that PKA and CREB molecules localize into subcellular organelles (8-13). Interestingly, PKA-anchoring proteins in dendrites have been shown to tether PKAII-␣ to the outer membrane of mitochondria (8). Furthermore, the localization of the Cat subunit of PKA, and Reg subunit I (RI) or II (RII), has been found in the mitochondrial matrix (6,(9)(10)(11)(12). CREB is also present in the mitochondria of the adult rat brain (7). Mitochondrial CREB has been implicated in plasticitydependent changes associated with behavioral training (8). Thus, the localization of PKA and CREB in the mitochondria raises the possibility that they may play a role in neuronal plasticity and cell survival by regulating mitochondrial function via the mitochondrial PKA and CREB-dependent pathway (13).Deferoxamine (DFO), an iron chelator and antioxidant, is neuroprotective, reducing the level of toxic radical species such as redox-reactive irons (14, 15). We have previously shown that neuronal protection from oxidative st...

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Section: Discussionmentioning

confidence: 80%

Antioxidants modulate mitochondrial PKA and increase CREB binding to D-loop DNA of the mitochondrial genome in neurons

Ryu

Lee

Impey³

et al. 2005

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

146

128

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“…Parallels between the phenotypic pathologies of these disorders and A-T are evident and suggest the possibility of similarities in some of the factors that contribute to disease progression. In spite of this, very few investigations have detailed iron studies in A-T disease (35)(36)(37). A study by Shackelford and coworkers (35) has reported nontransferrin bound iron, a highly reactive form of free iron, to be increased in A-T patients and Atm Ϫ/Ϫ mice.…”

Section: G558 Iron Loading and Oxidative Stress In Thementioning

confidence: 99%

“…Our data support this identification of increased body iron in A-T and further enhance the importance of this by showing significant changes in clinically relevant iron indexes. In vitro iron chelation studies using A-T cell models have also shown significant improvements in cell viability as a direct result of iron chelation, demonstrating that intracellular iron is a contributing factor in the progression of cell damage in these models (35)(36)(37). A potential link has been identified between increased iron and neurons in A-T as Hmox1, an enzyme involved in OS defense that produces labile iron as a byproduct (14,39) and which has been shown to be significantly upregulated in the cerebellum of 3-mo-old Atm Ϫ/Ϫ mice (3).…”

Section: G558 Iron Loading and Oxidative Stress In Thementioning

confidence: 99%

“…Shackelford and coworkers (35)(36)(37) have previously shown that the sera of Atm Ϫ/Ϫ mice contain more labile iron than that of wild-type mice, and that iron chelation in colonyforming experiments increased the colony-forming and survival capacity of A-T cells. Given the significance of OS to A-T disease pathology, and the high capacity of iron to affect OS, it is surprising that the regulation of iron homeostasis within the Atm Ϫ/Ϫ mouse has not been reported previously.…”

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confidence: 99%

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Iron loading and oxidative stress in theAtm^−/−mouse liver

McDonald

Ostini

Wallace

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Elevated labile iron in the substantia nigra pars compacta plays an important role in producing reactive oxygen species (ROS), mainly hydroxyl radicals, which subsequently damage nigro-striatal neurons. Interestingly, the iron chelator desferal increased the radio-resistance of ATM-deficient cells, but did not affect wild-type cells [71], leading the authors to hypothesize that ATM plays a role in cellular resistance to the toxic effects of labile iron. Collectively, these findings may explain the impression that A-T patients show ''Parkinsonian'' features [72].…”

Section: Nijmegen Breakage Syndromementioning

confidence: 99%

DNA damage, neuronal and glial cell death and neurodegeneration

Barzilai

2010

Apoptosis

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The DNA damage response (DDR) is a key factor in the maintenance of genome stability. As such, it is a central axis in sustaining cellular homeostasis in a variety of contexts: development, growth, differentiation, and maintenance of the normal life cycle of the cell. It is now clear that diverse mechanisms encompassing cell cycle regulation, repair pathways, many aspects of cellular metabolism, and cell death are inter-linked and act in concert in response to DNA damage. Defects in the DDR in proliferating cells can lead to cancer, while DDR defects in neurons may result in neurodegeneration. Mature neurons are highly differentiated, post-mitotic cells that cannot be replenished after disease or trauma. Their high metabolic activity generates large amounts of reactive oxygen species with DNA damaging capacity. Moreover, their intense transcriptional activity increases the potential for genomic DNA damage. Respectively, neurons have elaborate mechanisms to defend the integrity of their genome, thus ensuring their longevity and functionality in the face of these threats. Over the course of the past two decades, there has been a substantial increase in our understanding of the role of glial cells in supporting the neuronal cell DDR and longevity. This review article focuses on the potential role of the DDR in the etiology and pathogenesis of neurodegenerative diseases, and in addition, it describes various aspects of glial cell functionality in two genomic instability disorders: ataxia telangiectasia (A-T) and Nijmegen breakage syndrome.

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Desferrioxamine treatment increases the genomic stability of Ataxia-telangiectasia cells

Cited by 22 publications

References 23 publications

Antioxidants modulate mitochondrial PKA and increase CREB binding to D-loop DNA of the mitochondrial genome in neurons

Antioxidants modulate mitochondrial PKA and increase CREB binding to D-loop DNA of the mitochondrial genome in neurons

Iron loading and oxidative stress in theAtm^−/−mouse liver

DNA damage, neuronal and glial cell death and neurodegeneration

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Desferrioxamine treatment increases the genomic stability of Ataxia-telangiectasia cells

Cited by 22 publications

References 23 publications

Antioxidants modulate mitochondrial PKA and increase CREB binding to D-loop DNA of the mitochondrial genome in neurons

Antioxidants modulate mitochondrial PKA and increase CREB binding to D-loop DNA of the mitochondrial genome in neurons

Iron loading and oxidative stress in theAtm−/−mouse liver

DNA damage, neuronal and glial cell death and neurodegeneration

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Iron loading and oxidative stress in theAtm^−/−mouse liver