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

Abstract

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.

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Identifiers

ORCID for Joanna D Stewart: orcid.org/0000-0002-2608-1967

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