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Hematopoiesis in the thymidine kinase 2 deficient mouse model of mitochondrial DNA depletion syndrome

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Mitochondria are important for normal blood-cell development, and several diseases linked to mitochondrial DNA (mtDNA) show hematological manifestations. We recently generated a mouse strain deficient in expression of the mitochondrial pyrimidine nucleoside kinase thymidine kinase 2 (Tk2), showing that these mice exhibit progressive mtDNA depletion in multiple organs. We used this mouse strain as a model for mtDNA depletion syndromes to investigate the effects of mtDNA depletion on hematopoiesis. MtDNA levels in spleen from the Tk2-deficient mice were decreased 50%, but in contrast to all other investigated organs, both thymus and peripheral blood leukocytes showed normal mtDNA levels. Analysis of peripheral blood and cell populations in spleen, thymus, and bone marrow showed normal findings in the Tk2-deficient mice. The total rates of thymidine phosphorylation—which also include phosphorylation catalyzed by cytosolic Tk 1—in both spleen and thymus from wild-type mice were >50-fold higher than in liver, brain, and muscle. In summary, our data show that blood cells are less dependent on mitochondrial Tk2 compared with several other tissues and that these cells can synthesize deoxyribonucleotides required for mtDNA replication by alternative pathways such as phosphorylation of thymidine by cytosolic Tk1.

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Abbreviations

ConA:

concanavalin A

DGUOK:

deoxyguanosine kinase

dCyd:

deoxycytidine

dCK:

deoxycytidine kinase

dThd:

deoxythymidine

dNTP:

deoxyribonucleoside triphosphate

dTTP:

deoxythymidine triphosphate

LPS:

lipopolysaccharide

mtDNA:

mitochondrial DNA

p53R2:

p53-inducible ribonucleotide reductase subunit 2

RR:

ribonucleotide reductase

Tk1:

thymidine kinase 1

Tk2:

thymidine kinase 2

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Acknowledgements

This work was supported by grants from the Swedish Cancer Society.

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Authors and Affiliations

  1. Clinical Microbiology F68, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, SE-14186, Stockholm, Sweden

    Xiaoshan Zhou, Magnus Johansson, Nicola Solaroli & Anna Karlsson

  2. Clinical Research Center, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, SE-14186, Stockholm, Sweden

    Björn Rozell

  3. Center for Infectious Medicine and Center for Experimental Hematology, Department of Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, SE-14186, Stockholm, Sweden

    Alf Grandien

Authors
  1. Xiaoshan Zhou
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  2. Magnus Johansson
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  3. Nicola Solaroli
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  4. Björn Rozell
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  5. Alf Grandien
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  6. Anna Karlsson
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Corresponding author

Correspondence to Anna Karlsson.

Additional information

Communicated by: Wolfgang Sperl

Competing interest: None declared.

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Zhou, X., Johansson, M., Solaroli, N. et al. Hematopoiesis in the thymidine kinase 2 deficient mouse model of mitochondrial DNA depletion syndrome. J Inherit Metab Dis 33, 231–236 (2010). https://doi.org/10.1007/s10545-010-9102-x

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  • DOI: https://doi.org/10.1007/s10545-010-9102-x

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