The Matrix Peptide Exporter HAF-1 Signals a Mitochondrial UPR by Activating the Transcription Factor ZC376.7 in C. elegans

Kimmel Center for Biology and Medicine of the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.
Molecular cell (Impact Factor: 14.02). 02/2010; 37(4):529-40. DOI: 10.1016/j.molcel.2010.01.015
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Thomas Neubert, Sep 01, 2014
1 Follower
30 Reads
    • "Oxygen consumption assays were performed as described in Haynes et al. (2010) using a Clark type electrode (Braeckman et al., 2002). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondrial diseases and aging are associated with defects in the oxidative phosphorylation machinery (OXPHOS), which are the only complexes composed of proteins encoded by separate genomes. To better understand genome coordination and OXPHOS recovery during mitochondrial dysfunction, we examined ATFS-1, a transcription factor that regulates mitochondria-to-nuclear communication during the mitochondrial UPR, via ChIP-sequencing. Surprisingly, in addition to regulating mitochondrial chaperone, OXPHOS complex assembly factor, and glycolysis genes, ATFS-1 bound directly to OXPHOS gene promoters in both the nuclear and mitochondrial genomes. Interestingly, atfs-1 was required to limit the accumulation of OXPHOS transcripts during mitochondrial stress, which required accumulation of ATFS-1 in the nucleus and mitochondria. Because balanced ATFS-1 accumulation promoted OXPHOS complex assembly and function, our data suggest that ATFS-1 stimulates respiratory recovery by fine-tuning OXPHOS expression to match the capacity of the suboptimal protein-folding environment in stressed mitochondria, while simultaneously increasing proteostasis capacity. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular cell 03/2015; 58(1). DOI:10.1016/j.molcel.2015.02.008 · 14.02 Impact Factor
  • Source
    • "In addition, certain transporters are involved in the intracellular trafficking and compartmentalization of polypeptides across various cell membranes (Fig. 1): TAP translocates antigenic peptides into the ER, while the closely related ABC transport complex TAPL (ABCB9) has been identified as a lysosomal polypeptide transporter [43] [44] [45]. The mitochondrial ABC system MDL1 (ABCB10 in human) [46] has been proposed to be involved in antigen presentation of mitochondrial peptides [47] [48], and specialized ABC systems secrete lipid-modified peptides (pheromones) across the plasma membrane for cell–cell communication in yeast and Drosophila [49] [50]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Protein homeostasis results in a steady supply of peptides, which are further degraded to fuel protein synthesis or metabolic needs of the cell. In higher vertebrates, a small fraction of the resulting peptidome, however, is translocated into the ER lumen by the transporter associated with antigen processing (TAP). Antigenic peptides are guided to major histocompatibility complex class I (MHC I) molecules and are finally displayed on the cell surface, where they mount an adaptive immune response against viral infected or malignantly transformed cells. Here, we review the structural organization and the molecular mechanism of this specialized antigen translocon. We discuss how the ATP-binding cassette (ABC) transporter TAP communicates and cooperates within the multi-component peptide-loading machinery, mediating the proper assembly and editing of kinetically stable peptide/MHC I complexes. In light of its important role within the MHC I antigen processing pathway, TAP is a prime target for viral immune evasion strategies, and we summarize how this antigen translocation machinery is sabotaged by viral factors. Finally, we compare TAP with other ABC systems that facilitate peptide translocation.
    Journal of Molecular Biology 09/2014; 427(5). DOI:10.1016/j.jmb.2014.09.006 · 4.33 Impact Factor
  • Source
    • "The details of the C. elegans UPR mt are still being worked out, with several factors having been identified as necessary for full induction in response to different forms of mitochondrial stress. The HAF-1 peptide exporter (Haynes et al., 2010), the CLPP-1 protease (Haynes et al., 2007), a ubiquitin-like protein UBL-5 (Benedetti et al., 2006), and two transcription factors, DVE-1, and ATFS-1 (ZC376.7) were shown to be necessary for induction of hsp-60 p ::gfp in an uncharacterized mutant (referred to as zc32) showing constitutive activation of the reporter and for larval development in animals with high levels of mitochondrial stress (Haynes et al., 2007, 2010; Nargund et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The mitochondrial unfolded protein response is a conserved pathway that allows mitochondrial chaperones and other factors to be induced in response to mitochondrial dysfunction. Activation of this pathway has been proposed to underlie lifespan extension from knockdown or mutation of several nuclear encoded mitochondrial genes in Caenorhabditis elegans. In some cases, however, induction of the mitochondrial unfolded protein response is associated with a reduction of lifespan in both yeast and C. elegans. It also has yet to be demonstrated that induction of the mitochondrial unfolded protein response is sufficient to increase lifespan in the absence of overt mitochondrial dysfunction. In this perspective, we briefly review the evidence for and against a direct pro-longevity role of the mitochondrial unfolded protein response and suggest important areas of investigation for experimentally addressing this question.
    Experimental gerontology 08/2014; 56. DOI:10.1016/j.exger.2014.02.002 · 3.49 Impact Factor
Show more