Oxidative Stress Impairs Cell Death by Repressing the Nuclease Activity of Mitochondrial Endonuclease G
Jason L.J. Lin,
Akihisa Nakagawa,
Riley Skeen-Gaar,
Wei-Zen Yang,
Pei Zhao,
Zhe Zhang,
Xiao Ge,
Shohei Mitani,
Ding Xue,
Hanna S. Yuan
Affiliations
Jason L.J. Lin
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan 11529, ROC
Akihisa Nakagawa
Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA
Riley Skeen-Gaar
Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA
Wei-Zen Yang
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan 11529, ROC
Pei Zhao
School of Life Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing 100084, China
Zhe Zhang
School of Life Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing 100084, China
Xiao Ge
School of Life Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing 100084, China
Shohei Mitani
Department of Physiology, Tokyo Women’s Medical University School of Medicine, Tokyo 162-8666, Japan
Ding Xue
Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA
Hanna S. Yuan
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan 11529, ROC
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.
