SOD2-deficiency anemia: protein oxidation and altered protein expression reveal targets of damage, stress response, and antioxidant responsiveness

Friedman, Jeffrey S.; Lopez, Mary F.; Fleming, Mark D.; Rivera, Alicia; Martin, Florent; Welsh, Megan L.; Boyd, Ashleigh S.; Doctrow, Susan R.; Burakoff, Steven J.

doi:10.1182/blood-2003-11-3858

Cited by 157 publications

(134 citation statements)

References 51 publications

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“…This unique nature of erythrocytes in SOD1 −/− mice would cause them to be more vulnerable to ROS and shorten their lifespan. Anaemia was also observed in SOD2 +/+ mice with bone marrow transplanted from SOD2 −/− mice [22,30], but this could be caused by a defect in the process of differentiation to erythrocytes, because SOD2 is absent in erythrocytes. A deficiency in other antioxidative proteins, PrxI [31] and PrxII [32], which catalytically function as thioredoxindependent peroxidases, also causes anaemia by affecting the lifespan of erythrocytes.…”

Section: Discussionmentioning

confidence: 99%

“…The RBC lifespan was assayed by in vivo-and in vitro-biotinylation followed by FACS analyses [22]. RBCs were labelled with Abbreviations used: ALS, amyotrophic lateral sclerosis; CAII, carbonic anhydrase II; CAT, catalase; DCFH-DA, 2 ,7 -dichlorofluorescin diacetate; DHR123, dihydrorhodamine123; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GPX, glutathione peroxidase; GR, glutathione reductase; HRP, horseradish peroxidase; NAC, N-acetylcysteine; NHS-LC-biotin, N-succinimidyl-6-(biotinamide)hexanoate; Prx, peroxiredoxin; RBC, red blood cell; ROS, reactive oxygen species; SOD, superoxide dismutase; TBARS, thiobarbituric acid-reactive substances; TBS, Tris-buffered saline; TBST, Tris-buffered saline with Tween 20; TRX, thioredoxin.…”

Section: Rbc (Red Blood Cell) Turnover Assaymentioning

confidence: 99%

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Elevated oxidative stress in erythrocytes due to a SOD1 deficiency causes anaemia and triggers autoantibody production

Iuchi

Okada

Onuma

et al. 2007

Biochemical Journal

149

105

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Reactive oxygen species are involved in the aging process and diseases. Despite the important role of Cu/Zn SOD (superoxide dismutase) encoded by SOD1, SOD1 −/− mice appear to grow normally under conventional breeding conditions. In the present paper we report on a novel finding showing a distinct connection between oxidative stress in erythrocytes and the production of autoantibodies against erythrocytes in SOD1 −/− mice. Evidence is presented to show that SOD1 is primarily required for maintaining erythrocyte lifespan by suppressing oxidative stress. A SOD1 deficiency led to an increased erythrocyte vulnerability by the oxidative modification of proteins and lipids, resulting in anaemia and compensatory activation of erythropoiesis. The continuous destruction of oxidized erythrocytes appears to induce the formation of autoantibodies against certain erythrocyte components, e.g. carbonic anhydrase II, and the immune complex is deposited in the glomeruli. The administration of an antioxidant, N-acetylcysteine, suppressed erythrocyte oxidation, ameliorated the anaemia, and inhibited the production of autoantibodies. These data imply that a high level of oxidative stress in erythrocytes increases the production of autoantibodies, possibly leading to an autoimmune response, and that the intake of antioxidants would prevent certain autoimmune responses by maintaining an appropriate redox balance in erythrocytes.

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Section: Discussionmentioning

confidence: 99%

Section: Rbc (Red Blood Cell) Turnover Assaymentioning

confidence: 99%

Elevated oxidative stress in erythrocytes due to a SOD1 deficiency causes anaemia and triggers autoantibody production

Iuchi

Okada

Onuma

et al. 2007

Biochemical Journal

149

105

View full text Add to dashboard Cite

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“…In mice, sideroblastic anemias have been reproduced also by mutating the mitochondrial membrane protein, flexed tail (Fleming et al, 2001), and by deleting the antioxydant protein superoxide dismutase-2 that protects cells against mitochondrial superoxide (Friedman et al, 2004). In yeast, mitochondrial Fe accumulation with altered mitochondrial functions can be reproduced by mutating any of the enzymes of the (Fe-S) cluster assembly pathway (Lill and Kispal, 2000).…”

Section: Role Of Mitochondrial Iron Metabolism In Hematological Diseasesmentioning

confidence: 99%

Mitochondria in hematopoiesis and hematological diseases

et al. 2006

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“…Indeed, mitochondrial oxidative stress was found to play a key role in sideroblastic anemia and the myelodysplastic syndrome in humans and in zebrafish (29 -31). The importance of controlling ROS generation during erythropoiesis is also demonstrated by the severe hematopoietic phenotype of SOD2 null embryos and by the hemolytic anemia of the peroxiredoxin II null mice (32)(33)(34)(35)(36)(37). Additionally, it has been proposed that through uncoupling, UCP2 may facilitate heme synthesis by creating a local low oxygen environment in the mitochondrial matrix (29), thereby maintaining iron in the reduced ferrous iron (Fe 2ϩ ) state, keeping it available for ferrochelatase.…”

mentioning

confidence: 99%

UCP2 Modulates Cell Proliferation through the MAPK/ERK Pathway during Erythropoiesis and Has No Effect on Heme Biosynthesis

Elorza

Hyde

Mikkola

et al. 2008

Journal of Biological Chemistry

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UCP2, an inner membrane mitochondrial protein, has been implicated in bioenergetics and reactive oxygen species (ROS) modulation. High levels of UCP2 mRNA were recently found in erythroid cells where UCP2 is hypothesized to function as a facilitator of heme synthesis and iron metabolism by reducing ROS production. We examined UCP2 protein expression and role in mice erythropoiesis in vivo. UCP2 was mainly expressed at early stages of erythroid maturation when cells are not fully committed in heme synthesis. Iron incorporation into heme was unaltered in reticulocytes from UCP2-deficient mice. Although heme synthesis was not influenced by UCP2 deficiency, mice lacking UCP2 had a delayed recovery from chemically induced hemolytic anemia. Analysis of progenitor cells from bone marrow and fetal liver both in vitro and in vivo revealed that UCP2 deficiency results in a significant decrease in cell proliferation at the erythropoietin-dependent phase of erythropoiesis. This was accompanied by reduction in the phosphorylated form of ERK, a ROS-dependent cytosolic regulator of cell proliferation. Analysis of ROS in UCP2 null erythroid cells revealed altered distribution of ROS, resulting in decreased cytosolic and increased mitochondrial ROS. Restoration of the cytosol oxidative state of erythroid progenitor cells by the pro-oxidant Paraquat reversed the effect of UCP2 deficiency on cell proliferation in in vitro differentiation assays. Together, these results indicate that UCP2 is a regulator of erythropoiesis and suggests that inhibition of UCP2 function may contribute to the development of anemia.

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SOD2-deficiency anemia: protein oxidation and altered protein expression reveal targets of damage, stress response, and antioxidant responsiveness

Cited by 157 publications

References 51 publications

Elevated oxidative stress in erythrocytes due to a SOD1 deficiency causes anaemia and triggers autoantibody production

Elevated oxidative stress in erythrocytes due to a SOD1 deficiency causes anaemia and triggers autoantibody production

Mitochondria in hematopoiesis and hematological diseases

UCP2 Modulates Cell Proliferation through the MAPK/ERK Pathway during Erythropoiesis and Has No Effect on Heme Biosynthesis

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