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PLoS Genet. 2012;8(6):e1002760. doi: 10.1371/journal.pgen.1002760. Epub 2012 Jun 14.

Protective coupling of mitochondrial function and protein synthesis via the eIF2α kinase GCN-2.

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1
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.

Abstract

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).

PMID:
22719267
PMCID:
PMC3375257
DOI:
10.1371/journal.pgen.1002760
[Indexed for MEDLINE]
Free PMC Article
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