scholarly journals ATF4 helps mitochondria pass the stress test

2017 ◽  
Vol 216 (7) ◽  
pp. 1865-1865
Author(s):  
Ben Short
Keyword(s):  
Transcription Factor ◽  
Stress Response ◽  
Mammalian Cells ◽  
Stress Test ◽  
Mitochondrial Stress

The transcription factor ATF4 coordinates the mitochondrial stress response in mammalian cells.

scholarly journals Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals

2017 ◽  
Vol 216 (7) ◽  
pp. 2027-2045 ◽  
Author(s):  
Pedro M. Quirós ◽  
Miguel A. Prado ◽  
Nicola Zamboni ◽  
Davide D’Amico ◽  
Robert W. Williams ◽  
...  
Keyword(s):  
Stress Response ◽  
Mitochondrial Function ◽  
Mammalian Cells ◽  
Ribosomal Proteins ◽  
Cellular Metabolism ◽  
Mitochondrial Diseases ◽  
Mitochondrial Translation ◽  
Mitochondrial Stress ◽  
Main Regulator

Mitochondrial stress activates a mitonuclear response to safeguard and repair mitochondrial function and to adapt cellular metabolism to stress. Using a multiomics approach in mammalian cells treated with four types of mitochondrial stressors, we identify activating transcription factor 4 (ATF4) as the main regulator of the stress response. Surprisingly, canonical mitochondrial unfolded protein response genes mediated by ATF5 are not activated. Instead, ATF4 activates the expression of cytoprotective genes, which reprogram cellular metabolism through activation of the integrated stress response (ISR). Mitochondrial stress promotes a local proteostatic response by reducing mitochondrial ribosomal proteins, inhibiting mitochondrial translation, and coupling the activation of the ISR with the attenuation of mitochondrial function. Through a trans–expression quantitative trait locus analysis, we provide genetic evidence supporting a role for Fh1 in the control of Atf4 expression in mammals. Using gene expression data from mice and humans with mitochondrial diseases, we show that the ATF4 pathway is activated in vivo upon mitochondrial stress. Our data illustrate the value of a multiomics approach to characterize complex cellular networks and provide a versatile resource to identify new regulators of mitochondrial-related diseases.

scholarly journals A conserved role of CBP/p300 in mitochondrial stress response and longevity

2020 ◽  
Author(s):  
Terytty Yang Li ◽  
Maroun Bou Sleiman ◽  
Hao Li ◽  
Arwen W. Gao ◽  
Adrienne Mottis ◽  
...  
Keyword(s):  
Stress Response ◽  
Stress Responses ◽  
Mammalian Cells ◽  
Amyloid Β ◽  
Human Populations ◽  
Histone Demethylases ◽  
Mitochondrial Stress ◽  
Unfolded Protein ◽  
Evolutionarily Conserved ◽  
Protein Response

Abstract Organisms respond to mitochondrial stress by activating multiple defense pathways including the mitochondrial unfolded protein response (UPRmt). However, how different layers of UPRmt regulators are orchestrated to transcriptionally activate the stress responses remains largely unknown. Here we identified CBP-1, the worm ortholog of the mammalian acetyltransferases CBP/p300, as an essential regulator for UPRmt activation, as well as for mitochondrial stress-induced immune response, reduction of amyloid-β aggregation and lifespan extension in Caenorhabditis elegans. Mechanistically, CBP-1 acts downstream of histone demethylases, JMJD-1.2/JMJD-3.1, and upstream of UPRmt transcription factors including ATFS-1, to systematically induce a broad spectrum of UPRmt genes and execute multiple beneficial functions. In mouse and human populations, transcript levels of CBP/p300 positively correlate with UPRmt transcripts and longevity. Furthermore, CBP/p300 inhibition disrupts, while forced expression of p300 is sufficient to activate, the UPRmt in mammalian cells. These results highlight an evolutionarily conserved mechanism that determines mitochondrial stress response, and promotes health and longevity through CBP/p300.

scholarly journals Dynamic proteomics profiling of Legionella pneumophila infection unveils modulation of the host mitochondrial stress response pathway

2020 ◽  
Author(s):  
Julia Noack ◽  
David Jimenez-Morales ◽  
Erica Stevenson ◽  
Tom Moss ◽  
Gwendolyn Jang ◽  
...  
Keyword(s):  
Stress Response ◽  
Host Cell ◽  
Legionella Pneumophila ◽  
Mammalian Cells ◽  
Bacterial Pathogen ◽  
Effector Proteins ◽  
Mitochondrial Stress ◽  
Cellular Targets ◽  
Mitochondrial Proteome ◽  
Cell Proteome

SUMMARYThe human pathogen Legionella pneumophila (L.p.) secretes ~330 bacterial effector proteins into the host cell which interfere with numerous cellular pathways and often regulate host cell proteins through post-translational modifications. However, the cellular targets and functions of most L.p. effectors are not known. In order to obtain a global overview of potential targets of these effectors, we analyzed the host cell proteome, ubiquitinome, and phosphoproteome during L.p. infection. Our analysis reveals dramatic spatiotemporal changes in the host cell proteome that are dependent on the secretion of bacterial effectors. Strikingly, we show that L.p. substantially reshapes the mitochondrial proteome and modulates mitochondrial stress response pathways such as the mitochondrial unfolded protein response (UPRmt). To our knowledge, this is the first evidence of manipulation of the UPRmt by a bacterial pathogen in mammalian cells. In addition, we have identified a previously uncharacterized L.p. effector that is targeted to host cell mitochondria and protects mitochondrial network integrity during mitochondrial stress.

scholarly journals Mitochondrial dysfunction is signaled to the integrated stress response by OMA1, DELE1 and HRI

2019 ◽  
Author(s):  
Xiaoyan Guo ◽  
Giovanni Aviles ◽  
Yi Liu ◽  
Ruilin Tian ◽  
Bret A. Unger ◽  
...  
Keyword(s):  
Stress Response ◽  
Mitochondrial Dysfunction ◽  
Mammalian Cells ◽  
Fine Tuning ◽  
Integrated Stress Response ◽  
Inner Mitochondrial Membrane ◽  
Alternative Response ◽  
Mitochondrial Stress ◽  
Eif2α Phosphorylation ◽  
Eif2α Kinase

AbstractIn mammalian cells, mitochondrial dysfunction triggers the integrated stress response (ISR), in which eIF2α phosphorylation upregulates the transcription factor ATF4. However, how mitochondrial stress is relayed to the ISR is unknown. We found that HRI is the eIF2α kinase necessary and sufficient for this relay. Using an unbiased CRISPRi screen, we identified factors upstream of HRI: OMA1, a mitochondrial stress-activated protease, and DELE1, a little-characterized protein we found to be associated with the inner mitochondrial membrane. Mitochondrial stress stimulates the OMA1-dependent cleavage of DELE1, leading to its accumulation in the cytosol, where it interacts with HRI and activates its eIF2α kinase activity. Blockade of the OMA1-DELE1-HRI pathway is beneficial during some, but not all types of mitochondrial stress, and leads to an alternative response that induces specific molecular chaperones. Therefore, this pathway is a potential therapeutic target enabling fine-tuning of the ISR for beneficial outcomes in diseases involving mitochondrial dysfunction.

scholarly journals m5U54 tRNA Hypomodification by Lack of TRMT2A Drives the Generation of tRNA-Derived Small RNAs

2021 ◽  
Vol 22 (6) ◽  
pp. 2941
Author(s):  
Marisa Pereira ◽  
Diana R. Ribeiro ◽  
Miguel M. Pinheiro ◽  
Margarida Ferreira ◽  
Stefanie Kellner ◽  
...  
Keyword(s):  
Stress Response ◽  
Small Rnas ◽  
Mammalian Cells ◽  
Cellular Stress ◽  
Cellular Stress Response ◽  
Translation Regulation ◽  
Translation Efficiency ◽  
Down Regulation ◽  
Gene Expression Control ◽  
The Impact

Transfer RNA (tRNA) molecules contain various post-transcriptional modifications that are crucial for tRNA stability, translation efficiency, and fidelity. Besides their canonical roles in translation, tRNAs also originate tRNA-derived small RNAs (tsRNAs), a class of small non-coding RNAs with regulatory functions ranging from translation regulation to gene expression control and cellular stress response. Recent evidence indicates that tsRNAs are also modified, however, the impact of tRNA epitranscriptome deregulation on tsRNAs generation is only now beginning to be uncovered. The 5-methyluridine (m5U) modification at position 54 of cytosolic tRNAs is one of the most common and conserved tRNA modifications among species. The tRNA methyltransferase TRMT2A catalyzes this modification, but its biological role remains mostly unexplored. Here, we show that TRMT2A knockdown in human cells induces m5U54 tRNA hypomodification and tsRNA formation. More specifically, m5U54 hypomodification is followed by overexpression of the ribonuclease angiogenin (ANG) that cleaves tRNAs near the anticodon, resulting in accumulation of 5′tRNA-derived stress-induced RNAs (5′tiRNAs), namely 5′tiRNA-GlyGCC and 5′tiRNA-GluCTC, among others. Additionally, transcriptomic analysis confirms that down-regulation of TRMT2A and consequently m5U54 hypomodification impacts the cellular stress response and RNA stability, which is often correlated with tiRNA generation. Accordingly, exposure to oxidative stress conditions induces TRMT2A down-regulation and tiRNA formation in mammalian cells. These results establish a link between tRNA hypomethylation and ANG-dependent tsRNAs formation and unravel m5U54 as a tRNA cleavage protective mark.

scholarly journals NAC Transcription Factor PwNAC11 Activates ERD1 by Interaction with ABF3 and DREB2A to Enhance Drought Tolerance in Transgenic Arabidopsis

2021 ◽  
Vol 22 (13) ◽  
pp. 6952
Author(s):  
Mingxin Yu ◽  
Junling Liu ◽  
Bingshuai Du ◽  
Mengjuan Zhang ◽  
Aibin Wang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Drought Stress ◽  
Stress Response ◽  
Transcriptional Activation ◽  
Dominant Role ◽  
State Level ◽  
Energy Conversion Efficiency ◽  
Nac Transcription Factor ◽  
Wild Plants ◽  
Transgenic Lines

NAC (NAM, ATAF1/2, and CUC2) transcription factors are ubiquitously distributed in eukaryotes and play significant roles in stress response. However, the functional verifications of NACs in Picea (P.) wilsonii remain largely uncharacterized. Here, we identified the NAC transcription factor PwNAC11 as a mediator of drought stress, which was significantly upregulated in P. wilsonii under drought and abscisic acid (ABA) treatments. Yeast two-hybrid assays showed that both the full length and C-terminal of PwNAC11 had transcriptional activation activity and PwNAC11 protein cannot form a homodimer by itself. Subcellular observation demonstrated that PwNAC11 protein was located in nucleus. The overexpression of PwNAC11 in Arabidopsis obviously improved the tolerance to drought stress but delayed flowering time under nonstress conditions. The steady-state level of antioxidant enzymes’ activities and light energy conversion efficiency were significantly increased in PwNAC11 transgenic lines under dehydration compared to wild plants. PwNAC11 transgenic lines showed hypersensitivity to ABA and PwNAC11 activated the expression of the downstream gene ERD1 by binding to ABA-responsive elements (ABREs) instead of drought-responsive elements (DREs). Genetic evidence demonstrated that PwNAC11 physically interacted with an ABA-induced protein—ABRE Binding Factor3 (ABF3)—and promoted the activation of ERD1 promoter, which implied an ABA-dependent signaling cascade controlled by PwNAC11. In addition, qRT-PCR and yeast assays showed that an ABA-independent gene—DREB2A—was also probably involved in PwNAC11-mediated drought stress response. Taken together, our results provide the evidence that PwNAC11 plays a dominant role in plants positively responding to early drought stress and ABF3 and DREB2A synergistically regulate the expression of ERD1.

scholarly journals The Transcriptional Cascade in the Heat Stress Response of Arabidopsis Is Strictly Regulated at the Level of Transcription Factor Expression

2015 ◽  
Vol 28 (1) ◽  
pp. 181-201 ◽  
Author(s):  
Naohiko Ohama ◽  
Kazuya Kusakabe ◽  
Junya Mizoi ◽  
Huimei Zhao ◽  
Satoshi Kidokoro ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Heat Stress ◽  
Stress Response ◽  
Heat Stress Response ◽  
Factor Expression ◽  
Transcription Factor Expression

A Virtual Reality Version of the Trier Social Stress Test: A Pilot Study

2011 ◽  
Vol 20 (4) ◽  
pp. 325-336 ◽  
Author(s):  
Mattias Wallergård ◽  
Peter Jönsson ◽  
Gerd Johansson ◽  
Björn Karlson
Keyword(s):  
Virtual Reality ◽  
Stress Response ◽  
Pilot Study ◽  
Social Stress ◽  
Stress Test ◽  
Structured Interview ◽  
Trier Social Stress Test ◽  
Physiological Data ◽  
Virtual Humans ◽  
Arithmetic Task

One of the most common methods of inducing stress in the laboratory in order to examine the stress response in healthy and clinical populations is the Trier Social Stress Test (TSST). Briefly, the participant is asked to deliver a speech and to perform an arithmetic task in front of an evaluating committee. The committee, consisting of three trained actors, does not respond emotionally during the test, which makes the situation very stressful for the participant. One disadvantage of the TSST is that it can be difficult to hold the experimental conditions constant. In particular, it may be difficult for actors to hold their acting constant across all sessions. Furthermore, there are several practical problems and costs associated with hiring professional actors. A computerized version of the TSST using virtual humans could be a way to avoid these problems provided that it is able to induce a stress response similar to the one of the original TSST. The purpose of the present pilot study was therefore to investigate the stress response to a virtual reality (VR) version of the TSST visualized using an immersive VR system (VR-TSST). Seven healthy males with an average age of 24 years (range: 23–26 years) performed the VR-TSST. This included delivering a speech and performing an arithmetic task in front of an evaluating committee consisting of three virtual humans. The VR equipment was a CAVE equipped with stereoscopy and head tracking. ECG and respiration were recorded as well as the participant's behavior and comments. Afterward, a semi-structured interview was carried out. In general, the subjective and physiological data from the experiment indicated that the VR version of the TSST induced a stress response in the seven participants. In particular, the peak increase in heart rate was close to rates observed in studies using the traditional TSST with real actors. These results suggest that virtual humans visualized with an immersive VR system can be used to induce stress under laboratory conditions.

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