Mitochondrial unfolded-protein response (WP525)

Caenorhabditis elegans

"Mitochondria are required for numerous essential metabolic processes including the regulation of apoptosis; therefore, proper maintenance of the mitochondrial proteome is crucial. The protein-folding environment in mitochondria is challenged by organelle architecture, the presence of reactive oxygen species and the difficulties associated with assembly of the electron transport chain, which consists of components encoded by both the mitochondrial and the nuclear genomes. Mitochondria have dedicated molecular chaperones and proteases that promote proper protein folding, complex assembly and quality control. Work in cultured mammalian cells and Caenorhabditis elegans has yielded clues to the mechanisms linking perturbations in the protein-folding environment in the mitochondrial matrix to the expression of nuclear genes encoding mitochondrial proteins. Here, we review the current knowledge of this mitochondrial unfolded protein response (UPRmt), compare it with the better understood UPR of the endoplasmic reticulum and highlight its potential impact on development and disease." (Haynes and Ron 2010)


Martijn Van Iersel , Alex Pico , Thomas Kelder , Kristina Hanspers , Daniela Digles , Christian Grove , Martina Summer-Kutmon , Egon Willighagen , Karen Yook , and Eric Weitz


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Caenorhabditis elegans




Pathway Ontology

stress response pathway


Label Type Compact URI Comment
ATFS-1 Fragments Metabolite chebi:16670
Ethidium Bromide Metabolite chebi:4883
Paraquat Metabolite chebi:34905
Protein Fragments Metabolite chebi:16670
Protein Fragments Metabolite chebi:16670
hsp-60 GeneProduct wormbase:Y22D7AL.5
Lon Protease/ C34B2.6 GeneProduct wormbase:C34B2.6
dnj-10 GeneProduct wormbase:F22B7.5
ClpX-likeProtease/(K07A3.3) GeneProduct ensembl:WBGene00019461
hsp-6 GeneProduct wormbase:C37H5.8
ClpX-likeProtease/(D2030.2) GeneProduct ensembl:WBGene00008412
GSP-1 GeneProduct wormbase:F29F11.6 gsp-1 encodes a protein phosphatase homologous to the yeast phosphatase required for eIF2-alpha dephosphorylation.
eIF2-alpha(Y37E3.10) GeneProduct ensembl:WBGene00021351
TIMM-23 GeneProduct ncbigene:173041
eIF2-alpha(Y37E3.10) GeneProduct ensembl:WBGene00021351
DVE-1 GeneProduct wormbase:ZK1193.5
TOMM-40 Protein wormbase:C18E9.6
HSP-60 Protein wormbase:Y22D7AL.5
PHB-2 Protein wormbase:T24H7.1 PHB-2, along with PHB-1, forms the mitochondrial inner membrane Prohibitin complex which is implicated in assembly of components of the respiratory chain.
SPG-7 Protein wormbase:Y47G6A.10
GCN-2 Protein wormbase:Y81G3A.3
UBL-5 Protein wormbase:F46F11.4
CLPP-1 Protein wormbase:ZK970.2
ATFS-1 Protein wormbase:ZC376.7
HAF-1 Protein wormbase:C30H6.6 haf-1, a gene encoding a mitochondria-localized ATP-binding cassestte protein, is required for signaling within the mitochondrial unfolded protein response (UPTmt) and for coping with misfolded protein stress. Peptide efflux from isolated mitochondria was ATP dependent and required HAF-1 and the protease ClpP.
DVE-1 Protein wormbase:ZK1193.5
HSP-6 Protein wormbase:C37H5.8
ATFS-1 Protein wormbase:ZC376.7
ATFS-1 Protein wormbase:ZC376.7
HSP-60 Protein wormbase:Y22D7AL.5
HSP-6 Protein wormbase:C37H5.8
UBL-5 Protein wormbase:F46F11.4


  1. Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones. Yoneda T, Benedetti C, Urano F, Clark SG, Harding HP, Ron D. J Cell Sci. 2004 Aug 15;117(Pt 18):4055–66. PubMed Europe PMC Scholia
  2. Ubiquitin-like protein 5 positively regulates chaperone gene expression in the mitochondrial unfolded protein response. Benedetti C, Haynes CM, Yang Y, Harding HP, Ron D. Genetics. 2006 Sep;174(1):229–39. PubMed Europe PMC Scholia
  3. ClpP mediates activation of a mitochondrial unfolded protein response in C. elegans. Haynes CM, Petrova K, Benedetti C, Yang Y, Ron D. Dev Cell. 2007 Oct;13(4):467–80. PubMed Europe PMC Scholia
  4. Mitochondrial stress signaling: a pathway unfolds. Broadley SA, Hartl FU. Trends Cell Biol. 2008 Jan;18(1):1–4. PubMed Europe PMC Scholia
  5. The matrix peptide exporter HAF-1 signals a mitochondrial UPR by activating the transcription factor ZC376.7 in C. elegans. Haynes CM, Yang Y, Blais SP, Neubert TA, Ron D. Mol Cell. 2010 Feb 26;37(4):529–40. PubMed Europe PMC Scholia
  6. The mitochondrial UPR - protecting organelle protein homeostasis. Haynes CM, Ron D. J Cell Sci. 2010 Nov 15;123(Pt 22):3849–55. PubMed Europe PMC Scholia
  7. Signaling the mitochondrial unfolded protein response. Pellegrino MW, Nargund AM, Haynes CM. Biochim Biophys Acta. 2013 Feb;1833(2):410–6. PubMed Europe PMC Scholia
  8. Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Nargund AM, Pellegrino MW, Fiorese CJ, Baker BM, Haynes CM. Science. 2012 Aug 3;337(6094):587–90. PubMed Europe PMC Scholia
  9. Protective coupling of mitochondrial function and protein synthesis via the eIF2α kinase GCN-2. Baker BM, Nargund AM, Sun T, Haynes CM. PLoS Genet. 2012;8(6):e1002760. PubMed Europe PMC Scholia