The mitochondrial transporter ABC-me (ABCB10), a downstream target of GATA-1, is essential for erythropoiesis in vivo (original) (raw)

Cell Death & Differentiation volume 19, pages 1117–1126 (2012)Cite this article

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Abstract

The mitochondrial transporter ATP binding cassette mitochondrial erythroid (ABC-me/ABCB10) is highly induced during erythroid differentiation by GATA-1 and its overexpression increases hemoglobin production rates in vitro. However, the role of ABC-me in erythropoiesis in vivo is unknown. Here we report for the first time that erythrocyte development in mice requires ABC-me. ABC-me−/− mice die at day 12.5 of gestation, showing nearly complete eradication of primitive erythropoiesis and lack of hemoglobinized cells at day 10.5. ABC-me−/− erythroid cells fail to differentiate because they exhibit a marked increase in apoptosis, both in vivo and ex vivo. Erythroid precursors are particularly sensitive to oxidative stress and ABC-me in the heart and its yeast ortholog multidrug resistance-like 1 have been shown to protect against oxidative stress. Thus, we hypothesized that increased apoptosis in ABC-me−/− erythroid precursors was caused by oxidative stress. Within this context, ABC-me deletion causes an increase in mitochondrial superoxide production and protein carbonylation in erythroid precursors. Furthermore, treatment of ABC-me−/− erythroid progenitors with the mitochondrial antioxidant MnTBAP (superoxide dismutase 2 mimetic) supports survival, ex vivo differentiation and increased hemoglobin production. Altogether, our findings demonstrate that ABC-me is essential for erythropoiesis in vivo.

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Abbreviations

ABC-me:

ATP Binding Cassette-mitochondrial erythroid

SOD:

superoxide dismutase

ES:

embryonic stem cells

pc:

post coitus

ROS:

reactive oxygen species

MnTBAP:

Mn(III)tetrakis(4-benzoic acid)porphyrin

NAC:

_N_-acetyl-cysteine

FITC:

fluorescein isothiocyanate

PE:

phycoerythrin

TUNEL:

terminal deoxynucleotidyl transferase dUTP nick end labeling

BrdU:

bromodeoxiuridine

BCL-xL:

B-cell lymphoma extra large

Mfrn1:

mitoferrin 1

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Acknowledgements

We are grateful to Drs. Alex Sheftel, Prem Ponka, Solomon Graf, Carlo Brugnara, Thomas Langer and Roland Lill for fruitful discussions and advice. We thank Dr. Yuko Fujiwara for her advice on mouse pathology. We are grateful to Barry Paw for providing the Mfrn1 antibody. This work was supported by the National Institutes of Health Grants R01HL071629–03 and R01DK074778 (to OSS). ML is a recipient of a post-doctoral fellowship from Fundación Ramón Areces. We are thankful to Professor Daniel Dagan for comments on the manuscript.

Author Contributions

BBH, ML, AAE and LR performed research and analyzed the data; WQ and SEH performed research; ML and BBH wrote the paper; BBH, AEE, ML and OSS designed experiments and analyzed the data. TMS and HKM contributed with vital new reagents and analytical tools.

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Author notes

  1. B B Hyde and M Liesa: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Obesity and Nutrition section, Mitochondria ARC, Evans Biomedical Research Center, Boston University School of Medicine, Boston, MA, USA
    B B Hyde, M Liesa, A A Elorza, W Qiu, S E Haigh & O S Shirihai
  2. Department of Laboratory Animal Medicine, Tufts University, Boston, MA, USA
    L Richey
  3. Department of Molecular and Cellular Developmental Biology, UCLA, Los Angeles, CA, USA
    H K Mikkola
  4. Harvard Stem Cell Institute, Children's Hospital/Harvard Medical School, Boston, MA, USA
    T M Schlaeger

Authors

  1. B B Hyde
  2. M Liesa
  3. A A Elorza
  4. W Qiu
  5. S E Haigh
  6. L Richey
  7. H K Mikkola
  8. T M Schlaeger
  9. O S Shirihai

Corresponding author

Correspondence toO S Shirihai.

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The authors declare no conflict of interest.

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Edited by R De Maria

Supplementary Information accompanies the paper on Cell Death and Differentiation website

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Hyde, B., Liesa, M., Elorza, A. et al. The mitochondrial transporter ABC-me (ABCB10), a downstream target of GATA-1, is essential for erythropoiesis in vivo.Cell Death Differ 19, 1117–1126 (2012). https://doi.org/10.1038/cdd.2011.195

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