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The matrix peptide exporter HAF-1 signals a mitochondrial UPR by activating the transcription factor ZC376.7 in C. elegans.

Molecular cell | Feb 26, 2010

Genetic analyses previously implicated the matrix-localized protease ClpP in signaling the stress of protein misfolding in the mitochondrial matrix to activate nuclear-encoded mitochondrial chaperone genes in C. elegans (UPR(mt)). Here, we report that haf-1, a gene encoding a mitochondria-localized ATP-binding cassette protein, is required for signaling within the UPR(mt) and for coping with misfolded protein stress. Peptide efflux from isolated mitochondria was ATP dependent and required HAF-1 and the protease ClpP. Defective UPR(mt) signaling in the haf-1-deleted worms was associated with failure of the bZIP protein, ZC376.7, to localize to nuclei in worms with perturbed mitochondrial protein folding, whereas zc376.7(RNAi) strongly inhibited the UPR(mt). These observations suggest a simple model whereby perturbation of the protein-folding environment in the mitochondrial matrix promotes ClpP-mediated generation of peptides whose haf-1-dependent export from the matrix contributes to UPR(mt) signaling across the mitochondrial inner membrane.

Pubmed ID: 20188671 RIS Download

Mesh terms: ATP-Binding Cassette Transporters | Animals | Caenorhabditis elegans | Caenorhabditis elegans Proteins | Mitochondria | Mitochondrial Proteins | Protein Folding | RNA Interference | Signal Transduction | Transcription Factors | Unfolded Protein Response

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Associated grants

  • Agency: NIDDK NIH HHS, Id: R01 DK047119
  • Agency: NCRR NIH HHS, Id: RR017990
  • Agency: NIEHS NIH HHS, Id: R01 ES008681
  • Agency: NIEHS NIH HHS, Id: R01 ES008681-14
  • Agency: NIEHS NIH HHS, Id: ES08681
  • Agency: NIDDK NIH HHS, Id: R37 DK047119
  • Agency: NIDDK NIH HHS, Id: R37 DK047119-16
  • Agency: NINDS NIH HHS, Id: F32 NS050901
  • Agency: NINDS NIH HHS, Id: P30 NS050276
  • Agency: NINDS NIH HHS, Id: F32-NS050901
  • Agency: NIDDK NIH HHS, Id: DK47119
  • Agency: NINDS NIH HHS, Id: NS050279

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