Protective coupling of mitochondrial function and protein synthesis via the eIF2α kinase GCN-2.
Cells respond to defects in mitochondrial function by activating signaling pathways that restore homeostasis. The mitochondrial peptide exporter HAF-1 and the bZip transcription factor ATFS-1 represent one stress response pathway that regulates the transcription of mitochondrial chaperone genes during mitochondrial dysfunction. Here, we report that GCN-2, an eIF2α kinase that modulates cytosolic protein synthesis, functions in a complementary pathway to that of HAF-1 and ATFS-1. During mitochondrial dysfunction, GCN-2-dependent eIF2α phosphorylation is required for development as well as the lifespan extension observed in Caenorhabditis elegans. Reactive oxygen species (ROS) generated from dysfunctional mitochondria are required for GCN-2-dependent eIF2α phosphorylation but not ATFS-1 activation. Simultaneous deletion of ATFS-1 and GCN-2 compounds the developmental defects associated with mitochondrial stress, while stressed animals lacking GCN-2 display a greater dependence on ATFS-1 and stronger induction of mitochondrial chaperone genes. These findings are consistent with translational control and stress-dependent chaperone induction acting in complementary arms of the UPR(mt).
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
Brooke M
BM
Baker
Amrita M
AM
Nargund
Tiffany
T
Sun
Cole M
CM
Haynes
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018832:Molecular Chaperones; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000235:genetics; D017510:Protein Folding; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
C548052:ATFS-1 protein, C elegans; D018528:ATP-Binding Cassette Transporters; D029742:Caenorhabditis elegans Proteins; C548053:HAF-1 protein, C elegans; D018832:Molecular Chaperones; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D019892:eIF-2 Kinase