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 uprmt. © 2012 baker et al.