Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1812, Issue 3, Pages 321-325Publisher
ELSEVIER
DOI: 10.1016/j.bbadis.2010.11.012
Keywords
Mitochondria; Mitochondrial DNA; Depletion; Ethidium bromide
Funding
- Medical Research Council (UK)
- UK Parkinson's Disease Society
- UK NIHR Biomedical Research Centre for Ageing
- Wellcome Trust [074454/Z/04/Z]
- UK National Commissioning Group for Rare Mitochondrial Disorders of Adults and Children
- Deutsche Forschungsgemeinschaft [HO 2505/2-1, KU-911/15-1, TR3-A11, TR3-D12]
- Newcastle upon Tyne Hospitals NHS Charity [RES0211/7262]
- Academy of Medical Sciences (UK) [BH090164]
- BMBF [01GZ0704, 01GM0868]
- Medical Research Council [G0701386] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0509-10011] Funding Source: researchfish
- MRC [G0701386] Funding Source: UKRI
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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.
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