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Mitochondrial DNA depletion syndrome, a frequent cause of childhood (hepato)encephalomyopathies, is defined as a reduction of mitochondrial DNA copy number related to nuclear DNA. It was previously shown that mtDNA depletion can be prevented by dAMP/dGMP supplementation in deoxyguanosine kinase-deficient fibroblasts. We investigated myotubes of patients diagnosed with mtDNA depletion carrying pathogenic mutations inDGUOK, POLG1(Alpers syndrome) andTYMP. Differentiating myotubes of all patients and controls were supplemented with different doses of dAMP/dGMP or dAMP/dGMP/dCMP inTYMPdeficiency, and analysed for mtDNA/nDNA ratio and for cytochromecoxidase (COX) activity. Serum deprivation and myotube formation triggered a decrease in mtDNA copy number inDGUOKorPOLG1deficient myotubes, but not inTYMPdeficiency and healthy controls. Supplementation with dAMP/dGMP leads to a significant and reproducible rescue of mtDNA depletion inDGUOKdeficiency.POLG1deficient myotubes also showed a mild, not significant increase in mtDNA copy number. MtDNA depletion did not result in deficient COX staining inDGUOKandPOLG1-deficient myotubes. Treatment with ethidium bromide resulted in very severe depletion and absence of COX staining in all cell types, and no recovery was observed after supplementation with dAMP/dGMP. We show that supplementation with dAMP/dGMP increases mtDNA copy number significantly inDGUOKdeficient myotubes and, leads to a mild, non-significant improvement of mtDNA depletion inPOLG1deficiency. No adverse effect on mtDNA copy number was observed on high-dose supplementationin vitro. Further studies are needed to determine possible therapeutic implications of dAMP/dGMP supplementation forDGUOKdeficiencyin vivo.

In vitro supplementation with dAMP/dGMP leads to partial restoration of mtDNA levels in mitochondrial depletion syndromes