Mitochondrial dysfunction and altered protein homeostasis are associated with numerous developmental and age-related diseases as well as the general process of aging 
. The mitochondrial protein-folding environment is maintained by nuclear-encoded mitochondrial chaperones, which promote efficient protein folding, and proteases that degrade those proteins that fail to fold or oligomerize correctly 
. Protein folding is compartmentalized in eukaryotic cells and facilitated by compartment-specific folding machinery in the cytosol, endoplasmic reticulum (ER) and mitochondria. As threats to protein homeostasis affect the folding compartments differently, each compartment has dedicated stress responses or unfolded protein response (UPR) signaling pathways to transcriptionally regulate organelle-specific molecular chaperones and reduce the protein-folding load on the resident protein folding machinery.
Dysfunction and accumulation of misfolded proteins in the ER triggers a multi-pronged unfolded protein response (UPRER
) that combines the upregulation of molecular chaperones to accommodate the folding requirements in the organelle with a reduction of cytosolic translation and ER protein import 
. Activation of the transmembrane kinase PERK phosphorylates the cytosolic translation initiation factor eIF2α, thus attenuating general mRNA translation and reducing the load of incoming unfolded polypeptides 
. In a complementary branch of the UPRER
, the transcription factor XBP-1 is activated and mediates the induction of ER-resident chaperones 
. Thus, by coordinating signaling through parallel pathways, stress is relieved and organelle function restored. In contrast to these ER-protective mechanisms, signaling pathways that protect the mitochondrial protein-folding environment are only beginning to emerge.
Maintenance of mitochondrial metabolic function depends on the efficient assembly of the mitochondrial proteome, which is comprised of nuclear-encoded as well as mitochondrial-encoded polypeptides 
. Those proteins encoded by the nucleus are translated in the cytosol and post-translationally imported into mitochondria in an unfolded or unstructured state where they interact with the network of mitochondria-resident molecular chaperones. Failure of mitochondrial proteins to properly fold or oligomerize can result in electron transport chain (ETC) defects and accumulation of ROS, which further impacts additional mitochondrial activities including metabolic function. In order to respond to mitochondrial-specific stresses caused by the accumulation of unfolded proteins, depletion of mtDNA, defects in respiration or altered ROS metabolism, mitochondria have evolved stress response pathways that upregulate mitochondrial molecular chaperones to restore organelle homeostasis 
. One of these pathways, termed the mitochondrial unfolded protein response (UPRmt
), couples the status of the mitochondrial protein-folding environment to the transcription of mitochondrial chaperone genes 
. The complement of nuclear-encoded mitochondrial chaperones, such as mtHsp70 and HSP-60, assist in import, folding, and assembly of multi-protein complexes in the matrix and on the matrix side of the inner mitochondrial membrane 
. Increased levels of mitochondrial dysfunction perturb the balance between chaperones and their client proteins, leading to activation of the UPRmt
and upregulation of mitochondrial chaperone genes to re-establish homeostasis 
Our previous genetic studies in C. elegans
have identified several proteins required for signaling the response including the mitochondrial inner membrane-localized peptide transporter HAF-1 and the bZip transcription factor ZC376.7 
, which was recently renamed ATFS-1 (A
actor associated with S
tress-1). Mitochondrial dysfunction triggers the HAF-1-dependent nuclear accumulation of ATFS-1, resulting in the upregulation of mitochondrial chaperone genes including HSP-60 and mtHsp70. Activation of this pathway occurs in response to elevated levels of mitochondrial stress, which can be the result of accumulation of unfolded proteins beyond the capacity of mitochondrial molecular chaperones 
as well as increased levels of oxidative stress 
, respiratory chain dysfunction and by mtDNA depletion 
. Thus, this mitochondrial stress response pathway, although termed a UPR because of conceptual similarities with the XBP-1 branch of the UPRER
, responds to diverse insults to mitochondrial function.
In addition to chaperone induction, the UPRER
also mediates the attenuation of cytosolic translation to protect the ER during stress. Similarly, inhibition of cytosolic translation has been suggested to promote mitochondrial function in yeast and Drosophila
models of mitochondrial stress, although a potential regulatory mechanism(s) remained to be elucidated 
. Cytosolic translation attenuation via PERK-1-mediated eIF2α phosphorylation promotes ER function during stress by reducing the client load on ER-resident chaperones 
. Additionally, in C. elegans
genetic manipulations that reduce cytosolic translation rates provide resistance to numerous stresses including heat shock and also extend lifespan 
. Several signaling pathways are known to regulate translation rates in eukaryotic cells including TOR-regulated phosphorylation of S6 kinase and 4E-BP 
, however a mechanism to couple cytosolic translation rates to mitochondrial function has not been demonstrated.
Phosphorylation of eIF2α by four dedicated kinases (GCN2, PERK, HRI and PKR) serves to attenuate cytosolic translation in response to a variety of cellular stresses including starvation, oxidative stress, viral infection and unfolded protein stress in the ER 
, . In yeast and mammals, GCN-2 phosphorylates eIF2α in response to conditions of low free amino acid levels and oxidative stress 
. Here we describe experiments demonstrating that in C. elegans
, translation attenuation via GCN-2-dependent eIF2α phosphorylation acts in a responsive and adaptive protective pathway during mitochondrial stress to promote mitochondrial function. Phosphorylation levels of eIF2α are increased during mitochondrial stress, which requires ROS generated from dysfunctional mitochondria. Our data demonstrate that GCN-2-dependent translational control acts in a mitochondrial protective signaling pathway complementary to the regulation of mitochondrial chaperone gene expression mediated by HAF-1 and ATFS-1.