Oxidative Stress Impairs Cell Death by Repressing the Nuclease Activity of Mitochondrial Endonuclease G

Cell Rep. 2016 Jul 12;16(2):279-287. doi: 10.1016/j.celrep.2016.05.090. Epub 2016 Jun 23.

Abstract

Endonuclease G (EndoG) is a mitochondrial protein that is released from mitochondria and relocated into the nucleus to promote chromosomal DNA fragmentation during apoptosis. Here, we show that oxidative stress causes cell-death defects in C. elegans through an EndoG-mediated cell-death pathway. In response to high reactive oxygen species (ROS) levels, homodimeric CPS-6-the C. elegans homolog of EndoG-is dissociated into monomers with diminished nuclease activity. Conversely, the nuclease activity of CPS-6 is enhanced, and its dimeric structure is stabilized by its interaction with the worm AIF homolog, WAH-1, which shifts to disulfide cross-linked dimers under high ROS levels. CPS-6 thus acts as a ROS sensor to regulate the life and death of cells. Modulation of the EndoG dimer conformation could present an avenue for prevention and treatment of diseases resulting from oxidative stress.

Keywords: apoptosis; crystal structure; endonuclease G; mitochondria dysfunction; nuclease.

MeSH terms

  • Animals
  • Apoptosis*
  • Caenorhabditis elegans / cytology
  • Caenorhabditis elegans / enzymology*
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / metabolism*
  • Crystallography, X-Ray
  • Down-Regulation
  • Endodeoxyribonucleases / chemistry
  • Endodeoxyribonucleases / metabolism*
  • Enzyme Stability
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / metabolism*
  • Models, Molecular
  • Oxidation-Reduction
  • Oxidative Stress*
  • Protein Interaction Domains and Motifs
  • Protein Multimerization
  • Protein Structure, Quaternary

Substances

  • Caenorhabditis elegans Proteins
  • Cps-6 protein, C elegans
  • Mitochondrial Proteins
  • Wah-1 protein, C elegans
  • Endodeoxyribonucleases
  • endonuclease G