Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Protein homeostasis is maintained by proteasomes containing PSMB9 induced by EEF1A2 upon mitochondrial stress

ABSTRACT: Perturbed proteostasis and mitochondrial dysfunction are often associated with age-related diseases such as Alzheimer’s and Parkinson’s diseases. However, the link between them remains incompletely understood. Mitochondrial dysfunction causes proteostasis imbalance, and cells respond to restore proteostasis by increasing proteasome activity and molecular chaperons in yeast and C. elegans. Here, we demonstrate the presence of similar responses in humans. Mitochondrial dysfunction upregulates a small heat shock protein HSPB1 and an immunoproteasome subunit PSMB9 leading to an increase in proteasome activity. HSPB1 and PSMB9 are required to prevent protein aggregation upon mitochondrial dysfunction. Moreover, PSMB9 expression is dependent on a translation elongation factor EEF1A2, and PSMB9-containing proteasomes are located near mitochondria, enabling fast local degradation of aberrant proteins. Our findings put a step forward in understanding the stress response triggered by mitochondrial dysfunction, and may be useful for therapeutic strategies to prevent or delay the onset of age-related diseases and attenuate their progression.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

SUBMITTER: Remigiusz Serwa

LAB HEAD: Prof. Agnieszka Chacinska

PROVIDER: PXD031374 | Pride | 2023-07-03

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Similar Datasets

Shotgun measurements of proteome fractionations: mitochondria, aggregates, and soluble fraction of NDUFA11 KO and WT HEK293T cells

Project description:Perturbed proteostasis and mitochondrial dysfunction are often associated with age-related diseases such as Alzheimer’s and Parkinson’s diseases. However, the link between them remains incompletely understood. Mitochondrial dysfunction causes proteostasis imbalance, and cells respond to restore proteostasis by increasing proteasome activity and molecular chaperons in yeast and C. elegans. Here, we demonstrate the presence of similar responses in humans. Mitochondrial dysfunction upregulates a small heat shock protein HSPB1 and an immunoproteasome subunit PSMB9 leading to an increase in proteasome activity. HSPB1 and PSMB9 are required to prevent protein aggregation upon mitochondrial dysfunction. Moreover, PSMB9 expression is dependent on a translation elongation factor EEF1A2, and PSMB9-containing proteasomes are located near mitochondria, enabling fast local degradation of aberrant proteins. Our findings put a step forward in understanding the stress response triggered by mitochondrial dysfunction, and may be useful for therapeutic strategies to prevent or delay the onset of age-related diseases and attenuate their progression.

2023-07-03 | PXD038004 | Pride

Protein homeostasis is maintained by proteasomes containing PSMB9 induced by EEF1A2 upon mitochondrial stress

2023-07-04 | PXD031282 | Pride

Bulk mRNA sequencing of wildtype (WT) and mutator mouse embryonic fibroblasts (MEFs)

Project description:The proteasome is the main proteolytic system for targeted protein degradation in the cell. Its function is fine-tuned according to cellular needs. Inhibition of the respiratory chain impairs proteasome activity, regulation of proteasome function by mitochondrial metabolism, however, is unknown. Here, we demonstrate that mitochondrial dysfunction reduces the assembly and activity of the 26S proteasome. Defects in respiratory chain caused metabolic reprogramming of the Krebs cycle and deficiency in the amino acid aspartate resulting in reduced 26S proteasome function. Aspartate supplementation fully restored assembly and activity of 26S proteasome complexes. This metabolic reprogramming involved sensing of aspartate via the mTORC1 pathway and the mTORC1-dependent transcriptional activation of defined proteasome assembly factors. Metabolic regulation of 26S function was confirmed in patient-derived skin fibroblasts with respiratory dysfunction containing a single mitochondrial mutation. Importantly, treatment of primary human lung fibroblasts with the respiratory chain inhibitor and anti-diabetic drug metformin similarly reduced assembly and activity of 26S proteasome complexes, which was fully reversible and rescued by supplementation of aspartate or pyruvate. Of note, reduced 26S activity conferred increased resistance towards the proteasome inhibitor Bortezomib, which was reversible upon pyruvate supplementation. Our study uncovers a fundamental novel mechanism of how mitochondrial metabolism adaptively adjusts protein degradation by the proteasome. It thus unravels unexpected consequences of defective mitochondrial metabolism in disease or drug-targeted mitochondrial reprogramming for proteasomal protein degradation in the cell. As metabolic inhibition of proteasome function can be alleviated by treatment with aspartate or pyruvate, our results also have therapeutic implications.

2020-07-26 | GSE153983 | GEO

Supersulphide airway protection in viral and chronic lung diseases

Project description:Supersulphides (inorganic and organic sulphides with sulphur catenation) manifest diverse physiological functions. These supersulphides are mainly generated from mitochondrial cysteinyl-tRNA synthetase (CARS2) that functions as a principal cysteine persulphide synthase (CPERS). Here we found powerful protective functions of supersulphides in viral airway infections (influenza and COVID-19) and chronic lung diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and aged lungs. Enhanced supersulphide exhalation also occurred from human airways in COVID-19 as well as the hamster model of SARS-CoV-2 infection, as identified by breath supersulphur-omics that we developed herein. The lung damage related to oxidative stress and inflammation in mouse models of COPD, IPF, and ageing and the lethal effects that resulted were mitigated by endogenous supersulphides, supplied via CARS2/CPERS or exogenously by the supersulphide donor glutathione trisulphide. Our findings thus elucidated the airway protective role of supersulphides and their therapeutic potential in viral and chronic lung diseases.

2023-07-14 | PXD043607 | Pride

Mitochondrial dysfunction induces oxidative stress and an impaired ubiquitin proteasome system to trigger the pathogenesis of Frontal Fibrosing Alopecia (FFA)

Project description:Mitochondrial dysfunction is implicated in myriad diseases. However, there is no single platform that facilitates mapping of mitochondrial pathways and processes essential for health and those that are defective in disease. Here, we manually curated 1008 mitochondrial proteins to create a database of 31 mitochondrial pathways and processes and named the database as ‘MitoGyan’. ‘Gyan’ in Sanskrit means knowledge. We also developed a mitochondria associated metabolic pathways visualization tool called MitoCyc within HumanCyc. Using these novel resources and an integrated ‘Omics’ approach, we demonstrate that mitochondrial dysfunction occurs early in a rare, inflammatory hair disease called Frontal Fibrosing Alopecia (FFA). Transmission electron microscopy and mass spectrometry show morphological and functional changes in the mitochondria of FFA hair follicles. Our data suggests that mitochondrial dysfunction induces oxidative stress and an impairment of the ubiquitin proteasome system (UPS) in FFA. We propose that mitochondria-targeted antioxidants provide a new therapeutic strategy for FFA. Microarray analyses of FFA was undertaken to decipher pathophysiological pathways of FFA leading to disease intitiation and progression

2021-12-21 | GSE58934 | GEO

Clinical and molecular characteristics indicate mitochondrial dysfunction in Charcot-Marie-Tooth families with the AARS1 Arg326Trp mutation

Project description:Introduction Aminoacyl tRNA-synthetases are ubiquitously expressed enzymes that attach amino acids to their cognate tRNA molecule. Mutations in several of the aminoacyl tRNA-syntheases are described to cause peripheral neuropathy, i.e. AARS1, GARS1, HARS1, YARS1 and WARS1. The Alanyl-tRNA Synthetase (AARS) is encoded by the AARS1. Bi-allelic mutations have been described responsible for epileptic encephalopathy with persistent myelination defect, while mutation in a single allele cause Charcot-Marie-Tooth disease type 2 (CMT2). Do date it is uncertain how a single AARS1 mutation cause tissue specific neuropathy. Methods The AARS1 was sequenced by next-generation sequencing in probands. Family members were examined by Sanger sequencing. Blood samples from affected and healthy controls were used for quantitative RNA analysis, biochemical analysis of alanine, and proteomics. Results Three Norwegian CMT2 families carried the same novel heterozygous AARS1 variant (NM_001605.2:c.976C>T p.(Arg326Trp)). The three families consisted of in total 17 genetically examined family members, of which 11 individuals carried the AARS1 variant and six unaffected individuals did not carry the variant. All individuals carrying the AARS1 variant presented with a mild to moderately severe CMT2 phenotype with adult onset, except a man age 91 years (reported by his son). Label-free quantitative proteomic analysis of four affected individuals pointed towards an effect on the immune system, comprising proteins known to represent components of systemic response to chronic injury and inflammation. Interestingly, a wide-spread impact on mitochondrial dysfunction was identified. Specifically, the oxidative phosphorylation complexes I, IV and V were highly downregulated. Conclusion Three Norwegian CMT2 families with an AARS1 variant, suggests mitochondrial dysfunction in AARS1 neuropathy.

2022-10-14 | PXD023842 | Pride

Modulation of protease expression by PITX transcription factors regulates protein quality control during aging

Project description:Protein quality control is important for healthy aging and is dysregulated in several age-related diseases. The autophagy-lysosome and ubiquitin-proteasome systems are key for proteostasis but it remains largely unknown whether other proteolytic systems maintain protein quality control during aging. Here, we find that the expression of proteolytic enzymes (proteases/peptidases) distinct from the autophagy-lysosome and ubiquitin-proteasome systems declines during skeletal muscle aging in Drosophila. Age-dependent downregulation of proteases undermines proteostasis, as demonstrated by the increase in detergent-insoluble poly-ubiquitinated proteins and pathogenic huntingtin-polyQ in response to protease RNAi. Transcriptomic analysis identifies Ptx1, homologous to human PITX1/2/3, as a transcriptional regulator of proteases. Specifically, RNAi for Ptx1 increases the expression of age-downregulated proteases and improves protein quality. Moreover, muscle-specific expression of Ptx1 RNAi extends lifespan. These findings indicate that protein quality control is ensured during aging by autophagy/proteasome-independent proteases that degrade misfolded and aggregation-prone proteins and by their transcriptional modulator Ptx1.

2022-08-15 | GSE156346 | GEO

Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy

Project description:Autophagy selectively degrades aggregation-prone misfolded proteins caused by defective cellular proteostasis. However, the complexity of autophagy may prevent the full appreciation of how its modulation could be used as a therapeutic strategy in disease management. Here we define a molecular pathway through which recombinant interleukin-1 receptor antagonist (IL-1Ra, anakinra) affects cellular proteostasis independently from the IL-1 receptor (IL-1R1). Anakinra promoted H2O2-driven autophagy through a xenobiotic sensing pathway involving the aryl hydrocarbon receptor that, activated through the indoleamine 2,3-dioxygenase 1-kynurenine pathway, transcriptionally activates NADPH Oxidase 4 independent of the IL-1R1. By coupling the mitochondrial redox balance to autophagy, anakinra improved the dysregulated proteostasis network in murine and human cystic fibrosis. We anticipate that anakinra may represent a therapeutic option in addition to its IL-1R1 dependent anti-inflammatory properties by acting at the intersection of mitochondrial oxidative stress and autophagy with the capacity to restore conditions in which defective proteostasis leads to human disease.

2021-11-27 | GSE188809 | GEO

Proteotoxic stress induced by mRNA mistranslation leads to proteome aggregation and mitochondrial dysfunction in vertebrates.

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

Selective elimination of mitochondria mutations in the germline by genome editing

Project description:Currently there is no treatment for mitochondrial disease, a group of devastating inherited disorders caused by mutations in mitochondrial DNA (mtDNA). Here we report a strategy to prevent the germline transmission of mitochondrial diseases. This technique is based on the specific elimination of mutated mtDNA through the use of mitochondria targeted nucleases. Our approaches represent a potential therapeutic avenue for preventing the transgenerational transmission of human mitochondrial diseases caused by mutations in mtDNA. A total of 4 samples were analyzed. Test samples were compared to sex-matched reference samples.

2015-04-23 | E-GEOD-67371 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data