Intracellular iron, but not copper, plays a critical role in hydrogen peroxide-induced DNA Damage

Barbouti, Alexandra

doi:10.1016/s0891-5849(01)00608-6

Cited by 184 publications

(113 citation statements)

References 39 publications

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“…Since Zn 2ϩ and Cd 2ϩ are not redox-active metals, no ROS production was expected, but the production of ROS by Cu 2ϩ or Cu 1ϩ was a certain possibility. Under normal conditions, intracellular copper may not be redox-active since, at difference with iron, intracellular cooper is bound to chaperones, which results in little or none "free" copper available to redox reactions (4,8,38).…”

Section: Discussionmentioning

confidence: 99%

Iron-induced reactive oxygen species mediate transporter DMT1 endocytosis and iron uptake in intestinal epithelial cells

Esparza

Gerdtzen

Olivera-Nappa

et al. 2015

American Journal of Physiology-Cell Physiology

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Esparza A, Gerdtzen ZP, Olivera-Nappa A, Salgado JC, Núñez MT. Iron-induced reactive oxygen species mediate transporter DMT1 endocytosis and iron uptake in intestinal epithelial cells. Am J Physiol Cell Physiol 309: C558 -C567, 2015. First published August 19, 2015; doi:10.1152/ajpcell.00412.2014.-Recent evidence shows that iron induces the endocytosis of the iron transporter dimetal transporter 1 (DMT1) during intestinal absorption. We, and others, have proposed that iron-induced DMT1 internalization underlies the mucosal block phenomena, a regulatory response that downregulates intestinal iron uptake after a large oral dose of iron. In this work, we investigated the participation of reactive oxygen species (ROS) in the establishment of this response. By means of selective surface protein biotinylation of polarized Caco-2 cells, we determined the kinetics of DMT1 internalization from the apical membrane after an iron challenge. The initial decrease in DMT1 levels in the apical membrane induced by iron was followed at later times by increased levels of DMT1. Addition of Fe 2ϩ , but not of Cd 2ϩ , Zn 2ϩ , Cu 2ϩ , or Cu 1ϩ , induced the production of intracellular ROS, as detected by 2=,7=-dichlorofluorescein (DCF) fluorescence. Preincubation with the antioxidant N-acetyl-L-cysteine (NAC) resulted in increased DMT1 at the apical membrane before and after addition of iron. Similarly, preincubation with the hydroxyl radical scavenger dimethyl sulfoxide (DMSO) resulted in the enhanced presence of DMT1 at the apical membrane. The decrease of DMT1 levels at the apical membrane induced by iron was associated with decreased iron uptake rates. A kinetic mathematical model based on operational rate constants of DMT1 endocytosis and exocytosis is proposed. The model qualitatively captures the experimental observations and accurately describes the effect of iron, NAC, and DMSO on the apical distribution of DMT1. Taken together, our data suggest that iron uptake induces the production of ROS, which modify DMT1 endocytic cycling, thus changing the iron transport activity at the apical membrane. DMT1; iron; ROS; mucosal block; mathematical modeling IRON UPTAKE FROM THE INTESTINAL lumen is carried out by the iron/H ϩ cotransporter DMT1, which is present in the apical membrane of absorptive enterocytes. Four isoforms of DMT1 are generated by alternative splicing of the 5=-end exons (exons 1A or 1B) and of the 3=-end exons [exons 16 (or ϩIRE) or 17 (or ϪIRE)] (23). Enterocytes and Caco-2 cells express solely the 1A isoforms (23). Concurring with the presence of an IRE element in the 3=-flanking region, DMT1 expression is downregulated by high cell iron. Expression of the 1A/ϩIRE isoform makes cells particularly sensitive to cell iron levels; expression of the 1A/-IRE isoform yields cells that also responds to iron changes, whereas cells expressing the 1B/ϩIRE or the 1B/-IRE isoforms do not respond. Thus it is possible that the regulation of DMT1 expression involves two regulatory regions, one contained in exon 1A and another in t...

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Section: Discussionmentioning

confidence: 99%

Iron-induced reactive oxygen species mediate transporter DMT1 endocytosis and iron uptake in intestinal epithelial cells

Esparza

Gerdtzen

Olivera-Nappa

et al. 2015

American Journal of Physiology-Cell Physiology

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“…Ironically, however, the production of these anti-oxidants by Hmox1 also results in the release of iron, a strong pro-oxidant. Transition metals such as iron act as pro-oxidative molecules by catalyzing the conversion of weak reactive oxygen species such as H 2 O 2 to produce highly reactive hydroxyl radicals that cause significant oxidative damage (2). Within normally functioning cells, concurrent with the upregulation of Hmox1 in response to OS is the upregulation in expression of the iron exporter Ferroportin (Fpn) (41).…”

mentioning

confidence: 99%

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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“…In neuronal cells, glutamate caused Ca 2ϩ -mediated ROS production through mitochondrial dysfunction, leading to DNA damage, PARP-1 hyperactivation, and cell death. Furthermore, Ca 2ϩ chelators, such as BAPTA-AM, EGTA-AM, and Quin-2-AM, protected against other oxidative stress-induced apoptotic and necrotic cell death mechanisms (49,50). In these studies, Ca 2ϩ chelation did not directly inhibit PARP-1 activity, but rather prevented DNA damage by inhibiting ROS.…”

Section: Discussionmentioning

confidence: 93%

“…S2B). Importantly, at 3 Amol/L h-lap (fLD 50 for MCF-7 cells), DNA-PKcs was significantly activated (9 F 0.2 foci per cell) whereas ATM and g-H2AX were not as robustly activated (3.9 foci per cell F1.98 and 3.0 foci per cell F0.12, respectively). These data suggest that both HR and NHEJ are activated after h-lap exposure, but the predominant DNA repair pathway activated is NHEJ (Fig.…”

Section: Resultsmentioning

confidence: 99%

Internal Mass Motion for Spacecraft Dynamics and Control

Hall¹

2008

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. (From -To) REPORT DATE (DD-MM-YYYY) 01-03-2008 REPORT TYPE Annual Summary DATES COVERED SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTWe demonstrate that the NQO1-dependent reduction of β-lap caused ROS generation, DNA breaks, and triggered calcium (Ca2+)-dependent γ-H2AX formation and PARP-1 hyperactivation. PARP-1 hyperactivation was an integral part of cell death caused by this compound, causing NAD+ and ATP losses that suppressed DNA repair and caused cell death. PARP-1 inhibition or intracellular Ca2+ chelation protected cells from β-lap-induced cell death. Similarly, hydrogen peroxide (H2O2), but not N-Methly-N'-nitro-N-nitrosoguanidine (MNNG), caused Ca2+-mediated PARP-1 hyperactivation and death. Thus, Ca2+-mediated PARP-1 hyperactivation and death. Thus, Ca2+ appears to be an important co-factor in PARP-1 hyperactivation after ROS-induced DNA damage. To further explore DNA repair as a resistance factor(s) that might impede cell death, we explored the contribution of DNA double-strand break (DSB) repair following β-lap exposure. Β-Lap treatment resulted in the NQO1-dependent activation of the MRE11-Rad50-Nbs-1 (MRN) complex, as well as ATM Serine 1981, DNA-PKcs Theronine 2609, and Chk1 Serine 345 phosphorylation, indicative of ATR activation. These data suggested the simultaneous activation of both homologous recombination (HR) and non-homologous end joining (NHEJ) pathways. However, inhibition of NHEJ potentiated β-lap lethality. SUBJECT TERMSCalcium, non-caspase-mediated apoptosis, beta-lapachone, poly(ADP-ribose)polymerase-1, breast cancer, therapeutics, NQO1, DNA double-stranded breaks, non-homologous end joining

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Intracellular iron, but not copper, plays a critical role in hydrogen peroxide-induced DNA Damage

Cited by 184 publications

References 39 publications

Iron-induced reactive oxygen species mediate transporter DMT1 endocytosis and iron uptake in intestinal epithelial cells

Iron-induced reactive oxygen species mediate transporter DMT1 endocytosis and iron uptake in intestinal epithelial cells

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

Internal Mass Motion for Spacecraft Dynamics and Control

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Intracellular iron, but not copper, plays a critical role in hydrogen peroxide-induced DNA Damage

Cited by 184 publications

References 39 publications

Iron-induced reactive oxygen species mediate transporter DMT1 endocytosis and iron uptake in intestinal epithelial cells

Iron-induced reactive oxygen species mediate transporter DMT1 endocytosis and iron uptake in intestinal epithelial cells

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

Internal Mass Motion for Spacecraft Dynamics and Control

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