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Mitochondrial HSP90 is involved in cellular physiology

ABSTRACT: We generated TRAP1 KO in HeLa and observed extensive transcriptional reprogramming. The KO does not activate the canonical heat-shock response but an alternate transcriptional response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147486 | GEO | 2025/03/24

REPOSITORIES: GEO

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The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in maintaining mitochondrial metabolic homeostasis

Project description:The molecular chaperone TRAP1, the mitochondrial isoform of cytosolic HSP90, remains poorly understood with respect to its pivotal role in the regulation of mitochondrial metabolism. Most studies have found it to be an inhibitor of mitochondrial oxidative phosphorylation (OXPHOS) and an inducer of the Warburg phenotype of cancer cells. However, others have reported the opposite and there is no consensus on the relevant TRAP1 interactors. This calls for a more comprehensive analysis of the TRAP1 interactome and of how TRAP1 and mitochondrial metabolism mutually affect each other. We show that the disruption of the gene for TRAP1 in a panel of cell lines dysregulates OXPHOS by a metabolic rewiring that induces the anaplerotic utilization of glutamine metabolism to replenish TCA cycle intermediates. Restoration of wild-type levels of OXPHOS requires full-length TRAP1. Whereas the TRAP1 ATPase activity is dispensable for this function, it modulates the interactions of TRAP1 with various mitochondrial proteins. Quantitatively by far the major interactors of TRAP1 are the mitochondrial chaperones mtHSP70 and HSP60. However, we find that the most stable stoichiometric TRAP1 complex is a TRAP1 tetramer, whose levels change in response to both a decline or an increase in OXPHOS. Our work provides a roadmap for further investigations of how TRAP1 and its interactors such as the ATP synthase regulate cellular energy metabolism. Our results highlight that TRAP1 function in metabolism and cancer cannot be understood without a focus on TRAP1 tetramers as potentially the most relevant functional entity.

2020-01-16 | PXD015873 | Pride

The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in maintaining mitochondrial metabolic homeostasis

2020-01-16 | PXD015789 | Pride

Mitochondrial HSP90 is involved in cellular physiology

Project description:Mitochondrial HSP90 is involved in cellular physiology

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Transgenic Expression Of Mitochondrial Chaperone Trap1 Accelerates Prostate Cancer Development

Project description:Protein homeostasis, or proteostasis is critical for organelle function, including mitochondria, but its role in cancer is controversial. Here, we show that transgenic mice expressing the mitochondrial chaperone, TRAP1 in the prostate develop prostatic hyperplasia and cellular atypia. When examined on a Pten+/- background, a common alteration in prostate cancer patients, TRAP1 transgenic mice showed accelerated incidence of invasive prostatic adenocarcinoma, characterized by increased cell proliferation and reduced apoptosis, in situ. Conversely, homozygous deletion of TRAP1 delays prostatic tumorigenesis in Pten+/- mice, without affecting hyperplasia or prostatic intraepithelial neoplasia (PIN). Global RNA sequencing and reverse phase protein array profiling of Pten+/--TRAP1 transgenic tumors reveals modulation of oncogenic networks of cell proliferation, apoptosis, cell motility, DNA damage and metabolism. Mechanistically, reconstitution of Pten+/- prostatic epithelial cells with TRAP1 results in increased cell proliferation, reduced apoptosis, heightened cell invasion, and no changes in mitochondrial bioenergetics. Therefore, TRAP1 promotes invasive prostate cancer, and provides an “actionable” therapeutic target in patients with advanced disease.

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Coordinated regulation of protein synthesis and mitochondrial respiration by the molecular chaperone TRAP1 in cancer cells

Project description:Here we show that TRAP1 directly binds translation elongation factors, both inside and outside mitochondria, and slows down translation. TRAP1 overexpression or silencing affects the synthesis of respiratory complex components. Inside mitochondria, TRAP1 binds the Complex III core component UQCRC2 and regulates Complex III activity. This decreases respiration rate upon basal condition but allows sustained oxidative phosphorylation when glucose is limiting, a condition in which TRAP1-UQCRC2 binding is lost. In humans, TRAP1 is co-expressed with the mitochondrial translational machinery, which synthesize respiratory complex proteins. Altogether, our results show an unprecedented level of complexity in the regulation of cancer cell metabolism, in which mitochondrial and cytosolic protein synthesis are co-regulated with energetic metabolism through the contribution of a common molecular chaperone

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Co-targeting HSP90 alpha and CDK7 overcomes resistance against HSP90 inhibitors in BCR-ABL1+ leukemia cells

Project description:HSP90 inhibitors (HSP90i) have not entered routinely in the clinics, primarily due to the associated resistance via heat shock response (HSR) induction and dose limiting toxicity. In this study, we employed genetic KO and knockdown (KD) models of HSP90 isoforms (α and β) for extensive multi-omics-based in vitro and in vivo characterization and identified HSP90α as the primary driver of malignancy of the two isoforms in BCR-ABL1+ leukemia cells. Notably, combinatorial ex vivo drug sensitivity screenings identified CDK7 inhibitors (CDK7i) as drugs synergizing with HSP90α inhibition.

2024-01-26 | PXD041871 | Pride

The impact of Hsp90 upon the Candida albicans transcriptome during heat shock

Project description:aThese experiments address the effects of depleting Hsp90 upon the transcriptome of the major fungal pathogen, Candida albicans, during the heat shock response. The data show that key virulence factors are regulated in response to heat shock, and that Hsp90 exerts major effects on the heat shock transcriptome.a

2016-05-16 | E-MTAB-4075 | biostudies-arrayexpress

ADP-ribosylation of mitochondrial proteins is mediated by Neuralized-like protein 4 (NEURL4)

Project description:We profiled the transcriptomic changes in Hela N4-KO cells vs. WT cells

2022-01-31 | GSE183952 | GEO

Mutation in mitochondrial chaperone TRAP1 is responsible for male-specific autism

Project description:There is growing evidence of mitochondrial disturbance in autism spectrum disorders (ASD) but causative relations remain to be established. We identified postzygotic mozaicp.Q639* mutation in the TRAP1 gene encoding mitochondrial chaperone of the HSP90 family in ASD patient whose monozygotic twin brother was healthy. An additional survey of 176 unrelated ASD probands showed identical TRAP1 variant in a single male patient. We generated a knock-in Trap1 p.Q641*mouse which displayed behavioral abnormalities relevant for ASD, that were more pronounced in males. This effect was corroborated by gender-specific differences in synaptic plasticity and the density of synaptic mitochondria. Next we performed transcriptome profiling by sequencing of RNA isolated from hippocampi of WT, HET and MUT male and female mice

2024-03-01 | GSE226319 | GEO

PRC2 Inactivation Induces Primary Chemoresistance by Repressing Mitochondrial Apoptosis in T-ALL

Project description:The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. To fully exploit this finding, it will be important to understand the molecular genetic contexts responsible for the relative mitochondrial priming of chemotherapy-sensitive versus resistant cell populations. Here, we report that mitochondrial apoptosis resistance in T-cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical samples from children with T-ALL treated on recent Dana-Farber Cancer Institute or Children’s Oncology Group clinical trials, we found that loss-of-function mutations in any of three core components of PRC2 (EZH2, EED or SUZ12) were associated with resistance to mitochondrial apoptosis. In human T-ALL cells, PRC2 depletion induced resistance to apoptosis induction by multiple chemotherapeutics with distinct mechanisms of action, including dexamethasone, doxorubicin and vincristine. PRC2 loss induced apoptosis resistance via transcriptional upregulation of the LIM domain transcription factor CRIP2, and subsequent downstream upregulation of the mitochondrial chaperone TRAP1. Importantly, TRAP1 overexpression was necessary to induce resistance to chemotherapy-induced apoptosis downstream of PRC2 inactivation, and pharmacologic inhibition of TRAP1 synergized with dexamethasone and doxorubicin. These findings demonstrate the importance of relative mitochondrial apoptotic priming as a prognostic factor in T-ALL, and implicate mitochondrial chaperone function as a molecular determinant of response to cancer chemotherapy, suggesting a rationale for targeted therapeutic intervention.

2018-10-18 | GSE112147 | GEO

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