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Evaluation of Intracellular Location of Reactive Oxygen Species in Solea Senegalensis Spermatozoa
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Evaluation of Intracellular Location of Reactive Oxygen Species in Solea Senegalensis Spermatozoa

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

Hok Khim Fam1,2, Kunho Choi1,2, Lauren Fougner1,2

  • 1BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada.

Scientific Reports
|March 11, 2018
PubMed

Insights

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) repairs mitochondrial DNA (mtDNA) damage, preventing mutations and maintaining cellular respiration. Tdp1 deficiency impairs mitochondrial function, contributing to spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) pathology.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Tyrosyl-DNA phosphodiesterase 1 (Tdp1) repairs DNA termini, and its mutations cause spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1).
  • Tdp1 translocates to mitochondria under oxidative stress, suggesting a role in mitochondrial DNA (mtDNA) maintenance.

Purpose of the Study:

  • To investigate Tdp1's role in repairing mtDNA damage.
  • To determine if mtDNA damage triggers Tdp1's mitochondrial translocation.
  • To elucidate Tdp1's contribution to mitochondrial function and SCAN1 pathogenesis.

Main Methods:

  • Utilized Saccharomyces cerevisiae mutants, cultured mouse and human cells, and Tdp1 knockout mice.
  • Induced oxidative stress using H2O2 and rotenone to activate kinases P38 and ERK1.
  • Examined Tdp1 translocation via the TIM/TOM complex and its interaction with Ligase III within mitochondria.

Main Results:

  • Oxidative stress induced Tdp1 translocation to mitochondria independently of mtDNA damage.
  • Tdp1 interacted with Ligase III and reduced mtDNA mutations within mitochondria.
  • Tdp1-deficient tissues exhibited impaired mitochondrial respiration and decreased viability.

Conclusions:

  • Tdp1 actively repairs mtDNA, maintaining its integrity.
  • Tdp1's mitochondrial function is crucial for cellular respiration and viability.
  • Mitochondrial dysfunction due to Tdp1 deficiency contributes to SCAN1 pathology.

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