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

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE226319 | GEO | 2024/03/01

REPOSITORIES: GEO

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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.

2017-05-11 | GSE81316 | GEO

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

2023-12-07 | GSE141616 | GEO

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

TRAP1 silencing in HCT116 cells

Project description:Trascription profiling analysis was performed on HCT-116 cell lines transiently silenced with TRAP1 compared with scrumble

2014-11-15 | E-MTAB-2500 | biostudies-arrayexpress

TRAP1 gene silencing in MCF7 cell lines

Project description:Transcription profiling by array of MCF7 cell lines silenced with TRAP1 small interfering RNA compared with scramble

2017-06-30 | E-MTAB-3584 | biostudies-arrayexpress

Project description:TRAP1 is a HSP90 molecular chaperone involved in cancer cell adaptation to unfavorable environments and metabolic reprogramming. The role of TRAP1 in the adaptive response to hypoxia was investigated in human colorectal cancer.

2022-05-30 | E-MTAB-10563 | biostudies-arrayexpress

Total proteome analysis of WT vs TRAP1 KO in HCT-116 and HEK-293T cells grown on different carbon sources.

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. To characterize the impact of TRAP1 in maintaining the cellular proteome under different energy sources we carried out a label free quantitation (LFQ) MS analysis of the total cellular proteome with WT and KO HEK293T and HCT116 cells cultured with the three different cocktails of carbon sources (Glc + Pyr + Gln, Gal + Pyr only, Gln only). Linked manuscript : Abhinav Joshi, Li Dai, Yanxin Liu, Jungsoon Lee, Nastaran Mohammadi Ghahhari, Gregory Segala, Kristin Beebe, Francis T.F. Tsai, David A. Agard, Len Neckers, and Didier Picard* (*corresponding author).

2020-01-16 | PXD015828 | Pride

Inhibition of HDAC1/2 along with TRAP1 causes Synthetic Lethality in Glioblastoma Model Systems

Project description:Pan and selective HDAC inhibition is synthetically lethal with TRAP1 inhibition in various model systems of glioblastoma, including patient derived xenograft (PDX) cells. Mechanistically, this occurs through several mechanisms, including the induction of metabolic stress by interference with tumor cell energy metabolism accompanied by modulation of pro- and anti-apoptotic Bcl-2 family proteins and the induction of a cell death with apoptotic features.

2020-05-13 | GSE150395 | GEO

Sex-Specific Microglia Defects in the Neuroligin-4 Knock-Out Mouse Model of Autism Spectrum Disorder

Project description:Neuroligin-4 (NL4) loss-of-function mutations are strongly associated with monogenic heritable abnormalities linked with Autism Spectrum Disorder (ASD). NL4 mutation in mice causes ASD related alterations in both, the synaptic and behavioral phenotype. Since microglia closely regulate synaptic development and are implicated as key players in ASD development and progression, we here studied microglial properties in the NL4-/- mouse model. We show that loss of NL4 caused altered behavior and impaired hippocampal gamma oscillations predominantly in male mice. In parallel, microglial density, morphology, and response to injury specifically in the CA3 region of the hippocampus were altered in NL4-deficient males only. A transcriptomic and proteomic analysis revealed a strong impact of sexual dimorphism on molecular alterations in microglia of NL4-deficient compared to wildtype mice. Estrogen application in male NL4-/- animals partially restored the impaired social behavior and the altered microglial phenotype. Together, these results indicate that loss of NL4 affects not only neuronal network activity and behavior, but changes in addition the phenotype of microglia in a sex-specific manner that could be targeted by estrogen treatment.

2023-10-24 | PXD024325 | Pride

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