Ciprofloxacin impairs mitochondrial DNA replication initiation through inhibition of Topoisomerase 2

Nucleic Acids Res. 2018 Oct 12;46(18):9625-9636. doi: 10.1093/nar/gky793.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Ciprofloxacin / pharmacology*
  • DNA Replication / drug effects
  • DNA Topoisomerases, Type II / chemistry
  • DNA Topoisomerases, Type II / genetics*
  • DNA, Mitochondrial / drug effects*
  • DNA, Mitochondrial / genetics
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / genetics
  • Poly-ADP-Ribose Binding Proteins / chemistry
  • Poly-ADP-Ribose Binding Proteins / genetics*
  • Transcription, Genetic / drug effects


  • DNA, Mitochondrial
  • Poly-ADP-Ribose Binding Proteins
  • Ciprofloxacin
  • DNA Topoisomerases, Type II
  • TOP2A protein, human
  • TOP2B protein, human