Remdesivir triphosphate blocks DNA synthesis and increases exonucleolysis by the replicative mitochondrial DNA polymerase, Pol γ

Remdesivir does not affect mitochondrial DNA copy number or deletion mutation frequency in aged male rats

“…Remdesivir's in vivo effects on the mtDNA polymerase and its subsequent impact on mitochondrial genetics are just beginning to be understood. Our data do not support the hypothesis that remdesivir affects mtDNA in vivo, despite the varied in vitro findings and in vivo findings in young animals [22,23]. Moreover, although IV remdesivir in rhesus macaques, at a 10 therapeutic concentration of 1µM remdesivir, showed no significant reduction in mtDNA copy number, a higher therapeutic level ( 2 µM) resulted in a 26% decrease in mtDNA copy number [24].…”

“…The effects of remdesivir on the accumulation of mtDNA deletion mutations has received very little attention. In human neonatal dermal fibroblasts, remdesivir treatment did not induce the 4977 or “common” mtDNA deletion mutation [22]. As a lower mtDNA copy number predicts a higher mtDNA deletion mutation frequency in human skeletal muscle [29], we hypothesized that reductions in mtDNA copy number induced by remdesivir would result in increased mtDNA deletion mutation frequency.…”

“…At high doses, remdesivir was toxic to mitochondria in two human intestinal and liver cell lines [21]. Remdesivir impedes mitochondrial DNA polymerase gamma activity but stimulates exonucleolytic activity [22]. Despite this, remdesivir did not alter mitochondrial DNA copy number in human liver cells [23] or skeletal muscle fibroblast cells, but increased mtDNA copy number in human neonatal dermal fibroblasts [22].…”

“…Remdesivir impedes mitochondrial DNA polymerase gamma activity but stimulates exonucleolytic activity [22]. Despite this, remdesivir did not alter mitochondrial DNA copy number in human liver cells [23] or skeletal muscle fibroblast cells, but increased mtDNA copy number in human neonatal dermal fibroblasts [22]. Higher doses of remdesivir in rhesus monkeys resulted in a significant loss of mtDNA [24] in an unspecified tissue.…”

Heterozygous p.Y955C mutation in DNA polymerase γ leads to alterations in bioenergetics, complex I subunit expression, and mtDNA replication

“…11 E ). Recent reports have demonstrated the usefulness of using human cell lines to measure the mitochondrial safety of antiviral drugs such as molnupiravir, remdesivir, and others ( 90 , 91 , 92 , 93 , 94 ). While we have characterized the differential effects of a single stressor on Y955C and WT cells in this work, other antivirals, drugs, and environmental toxicants should be investigated in the future to determine potential POLG Y955C–toxicant interactions.…”