Evaluating and responding to mitochondrial dysfunction: The mitochondrial unfolded-protein response and beyond

Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
Trends in cell biology (Impact Factor: 12.01). 03/2013; 23(7). DOI: 10.1016/j.tcb.2013.02.002
Source: PubMed

ABSTRACT During development and cellular differentiation, tissue- and cell-specific programs mediate mitochondrial biogenesis to meet physiological needs. However, environmental and disease-associated factors can perturb mitochondrial activities, requiring cells to adapt to protect mitochondria and maintain cellular homeostasis. Several mitochondrion-to-nucleus signaling pathways, or retrograde responses, have been described, but the mechanisms by which mitochondrial stress or dysfunction is sensed to coordinate precisely the appropriate response has only recently begun to be understood. Recent studies of the mitochondrial unfolded-protein response (UPR(mt)) indicate that the cell monitors mitochondrial protein import efficiency as an indicator of mitochondrial function. Here, we review how the cell evaluates mitochondrial function and regulates transcriptional induction of the UPR(mt), adapts protein-synthesis rates and activates mitochondrial autophagy to promote mitochondrial function and cell survival during stress.

Download full-text


Available from: Cole M Haynes, Aug 12, 2015
18 Reads
    • "Because ATFS-1 has a nuclear localization sequence (NLS), it traffics to the nucleus and mediates the induction of protective genes including mitochondrial chaperones and proteases, antioxidant machinery, as well as components of the glycolysis pathway (Nargund et al., 2012). These findings suggest that the UPR mt serves to stabilize the mitochondrial protein-folding environment and upregulate a separate source of ATP production to promote survival and ultimately recover mitochondrial function (Haynes et al., 2013; Houtkooper et al., 2013; Nargund et al., 2012). However, the cellular processes affected by ATFS-1 and UPR mt activation have yet to be fully resolved. "
    [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 mammals and other organisms it is established that misfolded proteins are not only sensed in the cytosol, but also in the ER and in mitochondria to elicit UPRs (Richter et al., 2010; Walter and Ron, 2011; Haynes et al., 2013). Multiple lines of evidence support the existence of an ER UPR in Arabidopsis (Srivastava et al., 2014) (Figure 1), and compromising protein folding in the ER by exposing Chlamydomonas cells to DTT or tunicamycin also has been shown to induce the expression of genes encoding ER resident disulfide isomerases (Perez-Martin et al., 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Heat waves occurring at increased frequency as a consequence of global warming jeopardize crop yield safety. One way to encounter this problem is to genetically engineer crop plants toward increased thermotolerance. To identify entry points for genetic engineering, a thorough understanding of how plant cells perceive heat stress and respond to it is required. Using the unicellular green alga Chlamydomonas reinhardtii as a model system to study the fundamental mechanisms of the plant heat stress response has several advantages. Most prominent among them is the suitability of Chlamydomonas for studying stress responses system-wide and in a time-resolved manner under controlled conditions. Here we review current knowledge on how heat is sensed and signaled to trigger temporally and functionally grouped sub-responses termed response elements to prevent damage and to maintain cellular homeostasis in plant cells. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    The Plant Journal 03/2015; 82(3). DOI:10.1111/tpj.12816 · 5.97 Impact Factor
  • Source
    • "A universally conserved trigger for HS responses is the accumulation of unfolded proteins. In eukaryotes, these are known to be sensed in the cytosol, the endoplasmic reticulum (ER), and mitochondria and signaled to the nucleus to initiate appropriate transcriptional responses (Voellmy and Boellmann, 2007; Walter and Ron, 2011; Haynes et al., 2013). Recent work suggested that an unfolded protein response also exists in the chloroplast (Yu et al., 2012; Schmollinger et al., 2013; Ramundo et al., 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: We applied a top-down systems biology approach to understand how Chlamydomonas reinhardtii acclimates to long-term heat stress (HS) and recovers from it. For this, we shifted cells from 25 to 42°C for 24 h and back to 25°C for ≥8 h and monitored abundances of 1856 proteins/protein groups, 99 polar and 185 lipophilic metabolites, and cytological and photosynthesis parameters. Our data indicate that acclimation of Chlamydomonas to long-term HS consists of a temporally ordered, orchestrated implementation of response elements at various system levels. These comprise (1) cell cycle arrest; (2) catabolism of larger molecules to generate compounds with roles in stress protection; (3) accumulation of molecular chaperones to restore protein homeostasis together with compatible solutes; (4) redirection of photosynthetic energy and reducing power from the Calvin cycle to the de novo synthesis of saturated fatty acids to replace polyunsaturated ones in membrane lipids, which are deposited in lipid bodies; and
    The Plant Cell 11/2014; 26(11). DOI:10.1105/tpc.114.130997 · 9.34 Impact Factor
Show more