Hangas A, Aasumets K, Kekäläinen NJ, Paloheinä M, Pohjoismäki JL, Gerhold JM, Goffart S - "Ciprofloxacin impairs mitochondrial DNA replication initiation through inhibition of Topoisomerase 2" Nucleic Acids Res 46(18):9625-9636 (2018) doi: 10.1093/nar/gky793
https://academic.oup.com/nar/article/46/18/9625/5088042
Maintenance of topological homeostasis is vital for gene expression and genome replication in all organisms. Similar to other circular genomes, also mitochondrial DNA (mtDNA) is known to exist in various different topological forms, although their functional significance remains unknown. We report here that both known type II topoisomerases Top2α and Top2β are present in mammalian mitochondria, with especially Top2β regulating the supercoiling state of mtDNA. Loss of Top2β or its inhibition by ciprofloxacin results in accumulation of positively supercoiled mtDNA, followed by cessation of mitochondrial transcription and replication initiation, causing depletion of mtDNA copy number. These mitochondrial effects block both cell proliferation and differentiation, possibly explaining some of the side effects associated with fluoroquinolone antibiotics. Our results show for the first time the importance of topology for maintenance of mtDNA homeostasis and provide novel insight into the mitochondrial effects of fluoroquinolones.
SEE also:
Perrone CE, Takahashi KC, Williams GM - "Inhibition of human topoisomerase IIalpha by fluoroquinolones and ultraviolet A irradiation" Toxicol Sci 69(1):16-22 (2002). doi: 10.1093/toxsci/69.1.16
https://academic.oup.com/toxsci/article/69/1/16/1707336
"Alternatively, Martínez and Chignell (1998) reported that the DNA photocleavage activity of FQs is independent from the generation of reactive oxygen species and may result from the formation of a carbene intermediate at the C-8 position resulting from the loss of fluoride upon exposure to ultraviolet irradiation (UVA)."
Martinez LJ, Li G, Chignell CF - "Photogeneration of fluoride by the fluoroquinolone antimicrobial agents lomefloxacin and fleroxacin" Photochem Photobiol 65(3):599-602 (1997) doi: 10.1111/j.1751-1097.1997.tb08612.x.
"The photolysis (> 320 nm) of the fluoroquinolone antibacterial agents lomefloxacin and fleroxacin results in the loss of their F3 atoms as fluoride."
(Generation of fluoride by Ciprofloxcin degradation is now well established ---> defluorination)