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

• Mitochondrial EndoG/CPS-6 dimers shift to monomers under oxidating conditions
• The nuclease activity of EndoG/CPS-6 is diminished in response to high ROS levels
• AIF/WAH-1 acts as an antioxidant to stabilize the dimeric conformation of EndoG/CPS-6
• Oxidative stress impairs cell death through suppression of EndoG’s nuclease activity

SummaryEndonuclease 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.

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