Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Small heat shock proteins operate as molecular chaperones in the mitochondrial intermembrane space

ABSTRACT: Mitochondria are complex organelles with different compartments, each harboring their own protein quality control factors. While the chaperones of the mitochondrial matrix have been well characterized, it is poorly understood which chaperones protect the mitochondrial intermembrane space. We show that cytosolic small heat shock proteins are imported under basal conditions into the mitochondrial intermembrane space, where they operate as molecular chaperones. To identify chaperone substrates with MS/MS, we used a molecular trap variant of HSPB1/Hsp27 (S135F mutant). Through affinity-enrichment co-immunoprecipitation we identified significantly enriched substrates versus GFP-negative control.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Sara Dufour

LAB HEAD: Vincent Timmerman

PROVIDER: PXD038275 | Pride | 2022-12-12

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Similar Datasets

CLPB disaggregase dysfunction impacts the functional integrity of the proteolytic SPY complex

Project description:CLPB is a mitochondrial intermembrane space AAA+ domain–containing disaggregase. CLPB mutations are associated with 3-methylglutaconic aciduria and neutropenia; however, the molecular mechanism underscoring disease and the contribution of CLPB substrates to disease pathology remains unknown. Interactions between CLPB and mitochondrial quality control (QC) factors, including PARL and OPA1, have been reported, hinting at dysregulation of organelle QC in disease. Utilizing proteomic and biochemical approaches, we define a stress-specific aggregation phenotype in a CLPB-null environment and define the CLPB substrate profile. We show an interplay between intermembrane space proteins including CLPB, HAX1, HTRA2, and the inner membrane quality control proteins (STOML2, PARL, YME1L1; SPY complex), with CLPB deficiency impeding SPY complex function by virtue of protein aggregation in the intermembrane space. We conclude that there is an interdependency of mitochondrial QC components at the intermembrane space/inner membrane interface, and perturbations to this network may underscore CLPB disease pathology.

2024-01-18 | PXD042313 | Pride

Human Tim8a, Tim8b and Tim13 are auxiliary assembly factors of mature Complex IV

Project description:Human Tim8a and Tim8b are paralogous intermembrane space proteins of the small TIM chaperone family. Yeast small TIMs function in the trafficking of proteins to the outer and inner mitochondrial membranes. This putative import function for hTim8a and hTim8b has been challenged in human models, but their true molecular function in cells has not been defined. Likewise, why human cells possess two Tim8 proteins and any potential redundancy is not clear. We demonstrate that hTim8a and hTim8b function in the assembly of cytochrome c oxidase (Complex IV). Using affinity enrichment mass spectrometry, we catalogue the interaction network of hTim8a, hTim8b and hTim13, identifying subunits and assembly factors of the Complex IV COX2 module. hTim8-deficient cells have a COX2/COX3 module defect, albeit less severe than a COX17KO cell line, and exhibit an accumulation of the S2 subcomplex. This suggests that hTim8a and hTim8b are required for assembly of Complex IV via interactions with intermembrane-space exposed subunits. We propose hTim8-hTim13 complexes act as chaperones to stabilise the intermediate S3 subcomplex, promoting assembly of monomeric Complex IV.

2023-05-10 | PXD037906 | Pride

Inhibition of the mitochondrial disulfide relay system impairs liver cancer cell proliferation

Project description:Augmenter of liver regeneration (ALR) is a critical multi-isoform protein with its longer isoform, located in the mitochondrial intermembrane space, being part of the mitochondrial disulfide relay system (DRS). Upregulation of ALR was observed in multiple forms of cancer, among them hepatocellular carcinoma (HCC). To shed light into the ALR role in the DRS in HCC, we thus pharmacologically inhibited ALR, resulting in profound mitochondrial impairment and cancer cell proliferation deficits. These effects were mostly reversed by supplementation with bioavailable hemin b, linking the DRS, and specifically ALR function, to mitochondrial iron homeostasis. Since tumor cells are known for their increased iron demand and since increased iron levels in cancer are associated with poor clinical outcome, these results help to further advance the intricate relation between iron and mitochondria in liver cancer.

2022-02-17 | PXD026695 | Pride

Disrupting mitochondrial copper distribution inhibits leukemic stem cell self-renewal

Project description:Leukemic stem cells (LSC) rely on oxidative metabolism and are differentially sensitive to targeting mitochondrial pathways, which spares normal hematopoietic cells. A subset of mitochondrial proteins are folded in the intermembrane space via the mitochondrial intermembrane assembly (MIA) pathway. We found increased mRNA expression of MIA pathway substrates in acute myeloid leukemia (AML) stem cells. Therefore, we evaluated the effects of inhibiting this pathway in AML. Genetic and chemical inhibition of ALR reduces AML growth and viability, disrupts LSC self-renewal and induces their differentiation. ALR inhibition preferentially decreases its substrate COX17, a mitochondrial copper chaperone and knockdown of COX17 phenocopies ALR loss. Inhibiting ALR and COX17 increases mitochondrial copper levels which in turn inhibit S-Adenosylhomocysteine Hydrolase (SAHH) and lower levels of S-adenosylmethionine (SAM), DNA methylation, and chromatin accessibility to lower LSC viability. These results provide insight into mechanisms through which mitochondrial copper controls epigenetic status and viability of LSCs.

2020-04-14 | GSE146252 | GEO

The mitochondrial surface receptor Tom70 protects the cytosol against mitoprotein-induced stress

Project description:Most mitochondrial proteins are synthesized as precursor proteins in the cytosol and post-translationally transported into mitochondria. The mitochondrial surface protein Tom70 acts at the interface of the cytosol and mitochondria. In vitro import experiments identified Tom70 as targeting receptor, particularly for hydrophobic carriers. Using in vivo methods, we revisited the Tom70 function, confirming that it supports the biogenesis of carriers and other mitochondrial proteins which considerably expands the set of Tom70-dependent mitochondrial proteins. However, the crucial activity of Tom70 is its recruitment of cytosolic chaperones to the outer membrane. Surprisingly, tethering an unrelated chaperone-binding domain onto the mitochondrial surface complements most of the defects caused by the absence of Tom70. In vivo, small single spanning inner membrane proteins can be particularly problematic when present in excess and the chaperone-binding ability of Tom70 is crucial to suppress their proteotoxicity. Thus, the predominant function of Tom70 is more that of a cytosolic co-chaperone, and its role as mitochondria-specifying receptor apparently is of less immediate relevance.

2021-03-29 | PXD021173 | Pride

AIM32 is a dual-localized 2Fe-2S mitochondrial protein that functions in redox quality control

Project description:Maintaining redox homeostasis under normal and stress conditions in the mitochondrion is complex. We used mass spectrometry analysis to identify key proteins that interacted with the sulfhydryl oxidase Erv1 of the mitochondrial intermembrane space assembly (MIA) pathway. Results: Aim32, a thioredoxin-like [2Fe-2S] ferredoxin protein, was identified as an Erv1 binding partner. Aim32 interacted with additional proteins including redox protein Osm1 as well as protein import components Tim17, Tim23, and Tim22. Detailed and complementary localization studies showed that Aim32 resided in both the mitochondrial matrix and intermembrane space, placing it in a rare protein class that is dual-localized within mitochondria. Deletion of Aim32 or conserved cysteine residues that coordinate the Fe-S center resulted in an increased accumulation of proteins with aberrant disulfide linkages. In addition, the steady-state level of assembled TIM22, TIM23, and Oxa1 protein import complexes was decreased and a subset of the import complexes showed misassembly, among other phenotypes. Aim32 also bound to several mitochondrial proteins under non-reducing conditions, suggesting a function in maintaining the redox status of oxidized proteins by potentially targeting cysteine residues that may be sensitive to oxidation. Finally, Aim32 was required for growth in stress conditions and the mitochondrial genome was essential in strains that lacked Aim32. Innovation: Aim32 is uniquely localized to both the mitochondrial intermembrane space and matrix and functions in redox regulation with a potential role in quality control. Conclusion: Aim32 may be poised as a sensor to maintain the redox state by repairing oxidized cysteine residues in a broad range of mitochondrial proteins.

2022-02-16 | PXD021662 | Pride

Drosophila CNS mitochondrial DNA dysfunction microarray

Project description:Mitochondrial DNA (mtDNA) encodes essential components of the respiratory chain and loss of mtDNA leads to mitochondrial dysfunction and neurodegeneration. Mitochondrial transcription factor A (TFAM) is an essential component of mtDNA replication and a regulator of mitochondrial copy number in cells. Studies have shown that TFAM knockdown leads to mitochondrial dysfunction and respiratory chain deficiencies. ATP synthase is Complex V of the mitochondrial respiratory chain. It is driven by a proton gradient between the intermembrane space and the mitochondrial matrix and generates the majority of cellular ATP. The knockdown of coupling factor 6 (Cf6), one of the components of the proton channel F0, causes dysfunction in the complex, leading to mitochondrial dysfunction and respiratory chain deficiencies. Using gene expression analysis, we aimed to investigate the effects of mtDNA dysfunction in the CNS at the molecular level.

2013-12-20 | GSE53509 | GEO

Diverged Trypanosome MICOS as a Hub for Mitochondrial Cristae Shaping and Protein Import

Project description:The mitochondrial contact site and cristae organization system (MICOS) is a complex responsible for proper cristae formation. Empirical data about this ubiquitous complex is limited to opisthokont models (e.g. yeast), impeding understanding of its core properties and adaptation potential to diverse cellular milieus. To close this knowledge gap, we characterized MICOS from the diverged excavate Trypanosoma brucei. These results allow the definition of fundamental MICOS properties, such as its role in maintaining both cristae and contacts between the inner and outer membranes plus its extrusion into the intermembrane space. Yet, surprising differences with opisthokonts indicate that MICOS can assume different forms. T. brucei MICOS contains a novel subunit involved in the import of intermembrane space proteins, including respiratory chain complex assembly factors. We propose an evidence-based hypothesis that T. brucei MICOS populates cristae membranes with proteins needed for respiration, supported by the complex's even distribution in cristae

2018-09-13 | PXD009601 | Pride

Mapping the protein interactome of mitochondrial intermembrane space proteases identifies a novel function for HTRA2

Project description:Data contains LC-MS data of proximity-based biotin labeling assay (BioID) to generate the protein interaction network of mitochondrial intermembrane space proteases fused with BirAFlag (C-terminal tag) and expressed in T-REx HEK293 cells.

2018-11-14 | MSV000083140 | MassIVE

Raw data for mass spectrometry analysis of the effects of hypoxia on mitochondrial protein composition

Project description:This project wanted to demonstrate that mitoselfphagy degrades various mitochondrial proteins to a different extent. Therefore，we measured the levels of mitochondrial proteins under hypoxia by mass spectrometry analysis. After 24 hours of hypoxia, most mitochondrial proteins, locating at different mitochondrial compartments, were decreased to different extents relative to normoxic controls. After hypoxia, The certain mitochondrial proteins were increased, and some mitochondrial proteins remained almost unchanged. These data demonstrated that mitoselfphagy is different from traditional mitophagy that degrades the entire mitochondria, which degrades various mitochondrial proteins to a different extent.

2023-10-24 | PXD034375 | Pride

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