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Human Molecular Genetics, 2003, Vol. 12, No. 15 1839-1845
DOI: 10.1093/hmg/ddg192
© 2003 Oxford University Press

Mitochondrial DNA depletion can be prevented by dGMP and dAMP supplementation in a resting culture of deoxyguanosine kinase-deficient fibroblasts

Jan-Willem Taanman1,*, John R. Muddle1 and Ania C. Muntau2

1University Department of Clinical Neurosciences, Royal Free and University College Medical School, University College London, London, UK and 2Dr von Hauner Children's Hospital, Ludwig-Maximilians University, Munich, Germany

Received April 4, 2003; Revised May 15, 2003; Accepted May 24, 2003

Deoxyguanosine kinase is a constitutively expressed, mitochondrial enzyme of the deoxyribonucleoside salvage pathway. Deficiency of deoxyguanosine kinase causes early-onset, hepatocerebral mitochondrial DNA (mtDNA) depletion syndrome. To clarify the molecular mechanism of the disease, a skin fibroblast culture was studied from a patient carrying a homozygous nonsense mutation in the gene for deoxyguanosine kinase. In situ examination of DNA synthesis demonstrated that, although mtDNA synthesis is cell cycle independent in control fibroblasts, mtDNA synthesis occurs mainly during the S-phase in deoxyguanosine kinase-deficient cells. Consistent with this observation, it was found that the mtDNA content of exponentially growing, deoxyguanosine kinase-deficient cells is only mildly affected. When cycling is inhibited by serum-deprivation and cells are in a resting state, however, the mtDNA content drops considerably in deoxyguanosine kinase-deficient cells, yet remains stable in control fibroblasts. The decline in mtDNA content in resting, deoxyguanosine kinase-deficient cells can be prevented by dGMP and dAMP supplementation, providing conclusive evidence that substrate limitation triggers mtDNA depletion in deoxyguanosine kinase-deficient cells.

* To whom correspondence should be addressed at: University Department of Clinical Neurosciences, RFUCM, UCL, Rowland Hill Street, London NW3 2PF, UK. Tel: +44 2077940500, ext 5354; Fax: +44 2074726829; Email: j.taanman{at}rfc.ucl.ac.uk


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