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J. Biol. Chem., Vol. 283, Issue 45, 30461-30470, November 7, 2008

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

Alvaro Elorza¹, Brigham Hyde, Hanna K. Mikkola^¶, Sheila Collins^||2, and Orian S. Shirihai¹³

From the Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts 02111, ^¶Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, California 90095, and ^||The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, and Evans Biomedical Research Center, Boston University, Boston, Massachusetts 02118

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.

Received for publication, July 16, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grants 1-R01-DK-074778-01 and 5-R01-HL-071629-03. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1—S5 and Table 1.

¹ Supported by National Institutes of Health Grant 5-R01-HL-071629-03.

² Supported by National Institutes of Health Grant R01-DK-54024.

³ To whom correspondence should be addressed: Boston University, Evans Biomedical Research Center, 650 Albany St., Boston, MA 02118. Tel.: 617-230-8570; E-mail: Shirihai{at}bu.edu.

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