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POLG mutations cause decreased mitochondrial DNA repopulation rates following induced depletion in human fibroblasts

Lookup NU author(s): Joanna Stewart, Kamil Sitarz, Professor Rita HorvathORCiD, Dr Angela Pyle, Dr Patrick Yu Wai Man, Professor Robert Taylor, Dr David Samuels, Professor Patrick Chinnery


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Disorders of mitochondrial DNA (mtDNA) maintenance have emerged as an important cause of human genetic disease, but demonstrating the functional consequences of de novo mutations remains a major challenge. We studied the rate of depletion and repopulation of mtDNA in human fibroblasts exposed to ethidium bromide in patients with heterozygous POLG mutations. POLG2 and TK2 mutations. Ethidium bromide induced mtDNA depletion occurred at the same rate in human fibroblasts from patients and healthy controls. By contrast, the restoration of mtDNA levels was markedly delayed in fibroblasts from patients with compound heterozygous POLG mutations. Specific POLG2 and TK2 mutations did not delay mtDNA repopulation rates. These observations are consistent with the hypothesis that mutations in POLG impair mtDNA repopulation within intact cells, and provide a potential method of demonstrating the functional consequences of putative pathogenic alleles causing a defect of mtDNA synthesis. (C) 2010 Elsevier B.V. All rights reserved.

Publication metadata

Author(s): Stewart JD, Schoeler S, Sitarz KS, Horvath R, Hallmann K, Pyle A, Yu-Wai-Man P, Taylor RW, Samuels DC, Kunz WS, Chinnery PF

Publication type: Article

Publication status: Published

Journal: Biochimica et Biophysica Acta: Molecular Basis of Disease

Year: 2011

Volume: 1812

Issue: 3

Pages: 321-325

Print publication date: 01/03/2011

ISSN (print): 0925-4439

ISSN (electronic): 0006-3002

Publisher: Elsevier BV


DOI: 10.1016/j.bbadis.2010.11.012


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Funder referenceFunder name
Medical Research Council (UK)
UK National Commissioning Group for Rare Mitochondrial Disorders of Adults and Children
UK NIHR Biomedical Research Centre for Ageing
UK Parkinson's Disease Society
074454/Z/04/ZWellcome Trust
BH090164Academy of Medical Sciences (UK)
HO 2505/2-1Deutsche Forschungsgemeinschaft
KU-911/15-1Deutsche Forschungsgemeinschaft
RES0211/7262Newcastle upon Tyne Hospitals NHS Charity
TR3-A11Deutsche Forschungsgemeinschaft
TR3-D12Deutsche Forschungsgemeinschaft