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Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs

Sugako Oka1, Mizuki Ohno, Daisuke Tsuchimoto

  • 1Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.

The EMBO Journal
|January 12, 2008
PubMed

Insights

Oxidative stress causes DNA damage, leading to cell death. This study reveals distinct pathways for nuclear and mitochondrial DNA damage, involving specific enzymes and signaling cascades.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Oxidative stress induces DNA lesions like 8-oxoguanine (8-oxoG) in nuclear and mitochondrial DNA.
  • The specific DNA type (nuclear vs. mitochondrial) and execution pathways of oxidative stress-induced cell death remain unclear.

Purpose of the Study:

  • To elucidate the distinct roles of nuclear and mitochondrial DNA damage in oxidative stress-induced cell death.
  • To identify the molecular mechanisms and signaling pathways involved in these distinct cell death processes.

Main Methods:

  • Generation of OGG1-null mouse cells expressing nuclear or mitochondrial human 8-oxoG DNA glycosylase to selectively accumulate 8-oxoG.
  • Investigation of cell death pathways triggered by 8-oxoG accumulation in either nuclear or mitochondrial DNA.
  • Utilizing knockdown of adenine DNA glycosylase (MutY homolog) to assess its role in single-strand break accumulation.

Main Results:

  • Accumulation of 8-oxoG in nuclear DNA triggered PARP-dependent apoptosis-inducing factor translocation.
  • Accumulation of 8-oxoG in mitochondrial DNA induced mitochondrial dysfunction and calpain activation via Ca2+ release.
  • Both pathways were initiated by single-strand breaks (SSBs) resulting from adenine excision opposite 8-oxoG, and were suppressed by MutY homolog knockdown.

Conclusions:

  • Distinct cell death pathways are initiated by oxidative DNA damage in nuclear versus mitochondrial DNA.
  • Single-strand break accumulation, mediated by adenine excision, is a critical upstream event in both pathways.
  • Targeting these specific DNA repair and damage response pathways could offer therapeutic strategies for oxidative stress-related diseases.

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