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6-Thioguanine damages mitochondrial DNA and causes mitochondrial dysfunction in human cells

Ilse Daehn1, Reto Brem, Eva Barkauskaite

  • 1Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Herts, UK. ilse.daehn@mssm.edu

FEBS Letters
|November 9, 2011
PubMed

Insights

Thiopurines like 6-thioguanine (6-TG) accumulate in mitochondrial DNA (mtDNA), inhibiting its replication. Oxidized 6-TG in mtDNA, especially with UVA light, impairs mitochondrial function and contributes to cell death.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Thiopurines are anticancer and immunosuppressant drugs.
  • These drugs lead to the accumulation of 6-thioguanine (6-TG) in nuclear DNA.

Purpose of the Study:

  • To investigate the incorporation and effects of 6-TG in mitochondrial DNA (mtDNA).
  • To determine the role of mtDNA 6-TG in drug-induced cellular toxicity, particularly in combination with UVA radiation.

Main Methods:

  • Investigated 6-TG incorporation into mtDNA.
  • Assessed the impact of oxidized mtDNA 6-TG on DNA polymerase gamma (Pol-γ) activity.
  • Measured mtDNA transcription, mitochondrial protein levels, and mitochondrial function.
  • Examined the role of UVA radiation in oxidizing mtDNA 6-TG.
  • Compared the sensitivity of mtDNA-containing and mtDNA-depleted cells to 6-TG and UVA treatment.

Main Results:

  • 6-TG is incorporated into mtDNA and rapidly oxidized.
  • Oxidized mtDNA 6-TG inhibits DNA Pol-γ, reducing mtDNA replication.
  • Accumulation of oxidized 6-TG leads to decreased mtDNA transcription, lower mitochondrial protein levels, and impaired mitochondrial function.
  • UVA radiation promotes the oxidation of mtDNA 6-TG.
  • Cells lacking mtDNA are less sensitive to combined 6-TG and UVA treatment, suggesting mtDNA's role in photosensitization.

Conclusions:

  • Mitochondrial DNA is a target for 6-TG accumulation and oxidation.
  • Oxidized mtDNA 6-TG disrupts mitochondrial replication and function.
  • Mitochondrial 6-TG oxidation contributes to the photosensitizing effects of 6-TG combined with UVA radiation.

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