Cytosolic aggregation of mitochondrial proteins enhances degeneration of cellular homeostasis
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ABSTRACT:
PROVIDER: PRJNA613671 | ENA |
REPOSITORIES: ENA
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Project description:Protein misfolding and aggregation deregulate the proteostasis network and are hallmarks of cell degeneration processes associated with aging and human diseases. But how proteome aggregation causes cell degeneration remains controversial due to the lack of suitable methods for controlling proteome aggregation at the cellular and organismal levels. To overcome this limitation, we have generated zebrafish embryos that exhibit protein aggregation due to misincorporation of Serine (Ser) at non-cognate protein sites on a proteome wide scale. These mistranslating embryos display up regulation of the unfolded protein response (UPR) and the ubiquitin proteasome pathway (UPP), increased protein ubiquitination and down-regulation of protein biosynthesis. Proteome damage also induces major disruption of the mitochondrial network, accompanied by mitochondrial and nuclear DNA damage and accumulation of reactive oxygen species (ROS). Taken together, our data highlight important roles of gene translational accuracy in the maintenance of ER homeostasis, DNA damage, mitochondrial function and oxidative stress. We postulate that protein biosynthesis errors (PBE) contribute to proteome aggregation and are a main cause of mitochondrial disruption.
2018-01-29 | GSE50090 | GEO
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Project description:Eukaryotic cells have evolved extensive protein quality control mechanisms to remove faulty translation products. Here we show that yeast cells continually produce faulty mitochondrial polypeptides that stall on the ribosome during translation but are imported into the mitochondria. The cytosolic protein Vms1, together with the E3 ligase Ltn1, protects against the mitochondrial toxicity of these proteins and maintains cell viability under respiratory conditions. In the absence of these factors, stalled polypeptides aggregate after import and sequester critical mitochondrial chaperone and translation machinery. Aggregation depends on C-terminal alanyl/threonyl sequences (CAT-tails) that are attached to stalled polypeptides on 60S ribosomes by Rqc2. Vms1 binds to 60S ribosomes at the mitochondrial surface and antagonizes Rqc2, thereby facilitating import, impeding aggregation and directing aberrant polypeptides to intra-mitochondrial quality control. Vms1 is a key component of a rescue pathway for ribosome-stalled mitochondrial polypeptides that are inaccessible to ubiquitylation, due to coupling of translation and translocation.
2017-10-27 | PXD007800 | Pride
Project description:A loss of the checkpoint kinase ATM leads to impairments in the DNA damage response, and in humans causes cerebellar neurodegeneration, and a high risk to cancer. A loss of ATM is also associated with increased protein aggregation. The relevance and characteristics of this aggregation are still incompletely understood. Moreover, it is unclear to what extent other genotoxic conditions can trigger protein aggregation as well. Here, we show that targeting ATM, but also ATR or DNA topoisomerases result in a similar, widespread aggregation of a metastable, disease-associated subfraction of the proteome. Aggregation-prone model substrates, including expanded polyglutamine repeats, aggregate faster under these conditions. This increased aggregation results from an overload of chaperone systems, which lowers the cell-intrinsic threshold for proteins to aggregate. In line with this, we find that inhibition of the HSP70 chaperone system further exacerbates the increased protein aggregation. Moreover, we identify the molecular chaperone HSPB5 as a potent suppressor of it. Our findings reveal that various genotoxic conditions trigger protein aggregation, in a manner that is highly reminiscent of the widespread aggregation occurring in situations of proteotoxic stress and in proteinopathies.
2022-02-07 | GSE173940 | GEO
Project description:Defects in mitochondrial metabolism have been increasingly linked with age-onset protein misfolding diseases such as Alzheimerâs, Parkinsonâs, and Huntingtonâs. In response to protein folding stress, compartment-specific unfolded protein responses (UPRs) within the endoplasmic reticulum, mitochondria, and cytosol work in parallel to ensure cellular protein homeostasis. While perturbation of individual compartments can make other compartments more susceptible to protein stress, the cellular conditions that trigger cross-communication between the individual UPRs remain poorly understood. We have uncovered a conserved, robust mechanism linking mitochondrial protein homeostasis and the cytosolic folding environment through changes in lipid homeostasis. Metabolic restructuring caused by mitochondrial stress or small molecule activators trigger changes in gene expression coordinated uniquely by both the mitochondrial and cytosolic UPRs, protecting the cell from disease-associated proteins. Our data suggest an intricate and unique system of communication between UPRs in response to metabolic changes that could unveil new targets for diseases of protein misfolding. Because the induction of the MCSR due to hsp-6 RNAi required both hsf-1 and dve-1, key transcription factors required for the HSR and UPRmt, respectively, we asked which gene sets are coordinately regulated by both factors. We performed microarray analyses to determine which genes have their expression altered by hsp-6 RNAi and whether these genes are regulated either by hsf-1, dve-1 or both
2016-09-08 | E-GEOD-83722 | biostudies-arrayexpress
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Project description:Defects in mitochondrial metabolism have been increasingly linked with age-onset protein misfolding diseases such as Alzheimer’s, Parkinson’s, and Huntington’s. In response to protein folding stress, compartment-specific unfolded protein responses (UPRs) within the endoplasmic reticulum, mitochondria, and cytosol work in parallel to ensure cellular protein homeostasis. While perturbation of individual compartments can make other compartments more susceptible to protein stress, the cellular conditions that trigger cross-communication between the individual UPRs remain poorly understood. We have uncovered a conserved, robust mechanism linking mitochondrial protein homeostasis and the cytosolic folding environment through changes in lipid homeostasis. Metabolic restructuring caused by mitochondrial stress or small molecule activators trigger changes in gene expression coordinated uniquely by both the mitochondrial and cytosolic UPRs, protecting the cell from disease-associated proteins. Our data suggest an intricate and unique system of communication between UPRs in response to metabolic changes that could unveil new targets for diseases of protein misfolding.
2016-09-08 | GSE83722 | GEO
Project description:When mutant superoxide dismutase 1 (SOD1) was first linked to amyotrophic lateral sclerosis (ALS), it was thought that ALS is a disease of oxidative stress, but this idea has taken a back seat since the discovery of multiple ALS-linked genes involved in RNA processing and proteostasis. Strikingly, a hallmark of both familial and sporadic ALS is the aggregation of the essential DNA/RNA binding protein TDP-43, which is thought to cause simultaneous loss-of-nuclear function and gain-of-cytoplasmic toxicity. A central unanswered question is what triggers ALS in adult followed by rapid and irreversible progression? Here we report that neuronal cells are particularly prone to oxidative stress to trigger TDP-43 aggregation, which in turn sponges a large subset of microRNAs and proteins, resulting in global mitochondrial imbalance that further elevates the oxidative stress. We propose that this ferocious cycle may underlie ALS onset and progression with oxidative stress as a key disease-driving event.
2020-10-12 | GSE126801 | GEO
Project description: Not available
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