Reactive oxygen species stress increases accumulation of tyrosyl-DNA phsosphodiesterase 1 within mitochondria

Sci Rep. 2018 Mar 9;8(1):4304. doi: 10.1038/s41598-018-22547-8.


Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a nuclear and mitochondrial protein that in nuclei and in vitro repairs blocked 3' DNA termini such as 3' phosphotyrosine conjugates resulting from stalling of topoisomerase I-DNA intermediates. Its mutation also causes spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1). Because Tdp1 colocalizes with mitochondria following oxidative stress, we hypothesized that Tdp1 repairs mitochondrial DNA (mtDNA) and that mtDNA damage mediates entry of Tdp1 into the mitochondria. To test this, we used S. cerevisiae mutants, cultured mouse and human cells, and a Tdp1 knockout mouse. H2O2- and rotenone-induced cellular and intramitochondrial reactive oxygen species (ROS) activated oxidant-responsive kinases P38 and ERK1, and the translocation of Tdp1 from the nucleus to the mitochondria via the TIM/TOM complex. This translocation occurred independently of mtDNA. Within the mitochondria, Tdp1 interacted with Ligase III and reduced mtDNA mutations. Tdp1-deficient tissues had impaired mitochondrial respiration and decreased viability. These observations suggest that Tdp1 maintains mtDNA integrity and support the hypothesis that mitochondrial dysfunction contributes to the pathology of SCAN1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Cell Line
  • Cell Nucleus / metabolism
  • Cell Respiration
  • Cells, Cultured
  • Humans
  • Mice
  • Mitochondria / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Oxidative Stress*
  • Phosphoric Diester Hydrolases / metabolism*
  • Reactive Oxygen Species / metabolism*
  • Saccharomyces cerevisiae
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Reactive Oxygen Species
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • Phosphoric Diester Hydrolases
  • TDP1 protein, human

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