Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A chaperone-assisted mechanism of outer mitochondrial membrane TOM70 insertion protective against diet-induced obesity

ABSTRACT: Outer mitochondrial membrane (OMM) proteins communicate with the cytosol and other organelles including the endoplasmic reticulum (ER). This communication is important in thermogenic adipocytes to increase energy expenditure that controls body temperature and weight. However, the regulatory mechanisms of OMM protein insertion are poorly understood. Herein, stress-induced cytosolic chaperone PPID (peptidyl-prolyl isomerase D/cyclophilin 40/Cyp40) drives OMM insertion of the mitochondrial import receptor TOM70 regulating body temperature and weight in obese mice, and respiratory/thermogenic function in brown adipocytes. PPID PPIase activity and C-terminal tetratricopeptide repeats (TPR), which show specificity towards TOM70 core and C-tail domains, facilitate OMM insertion. Our results provide an unprecedented role for ER-stress-activated chaperones in controlling energy metabolism through a selective OMM protein insertion mechanism with implications in adaptation to cold temperatures and high-calorie diets.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Anna Schmoker

LAB HEAD: Pere Puigserver

PROVIDER: PXD053607 | Pride | 2024-10-03

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	PPID_TOM.fasta	Fasta
	PPID_TOM_con_2023.07.06.filtered_cross-linked_spectra.csv	Csv
	PPID_TOM_con_2023.07.06.filtered_regular_spectra.csv	Csv
	cpd_5853A.mgf	Mgf
	cpd_5853A.raw	Raw

Items per page:

1 - 5 of 5

Similar Datasets

A chaperone-assisted mechanism of outer mitochondrial membrane TOM70 insertion protective against diet-induced obesity

Project description:Outer mitochondrial membrane (OMM) proteins communicate with the cytosol and other organelles including the endoplasmic reticulum (ER). This communication is important in thermogenic adipocytes to increase energy expenditure that controls body temperature and weight. However, the regulatory mechanisms of OMM protein insertion are poorly understood. Herein, stress-induced cytosolic chaperone PPID (peptidyl-prolyl isomerase D/cyclophilin 40/Cyp40) drives OMM insertion of the mitochondrial import receptor TOM70 regulating body temperature and weight in obese mice, and respiratory/thermogenic function in brown adipocytes. PPID PPIase activity and C-terminal tetratricopeptide repeats (TPR), which show specificity towards TOM70 core and C-tail domains, facilitate OMM insertion. Our results provide an unprecedented role for ER-stress-activated chaperones in controlling energy metabolism through a selective OMM protein insertion mechanism with implications in adaptation to cold temperatures and high-calorie diets.

2024-10-02 | PXD055263 | Pride

A chaperone-assisted mechanism of outer mitochondrial membrane TOM70 insertion protective against diet-induced obesity

2024-10-02 | PXD054182 | Pride

Mitochondria shed large SPOTs during infection-induced import stress to remodel their outer membrane

Project description:Despite the essential role of the outer mitochondrial membrane (OMM) in cellular homeostasis, little is known of the mechanisms that remodel it during naturally occurring stresses. Here, we report a previously undescribed structure we term SPOT (structure positive for outer mitochondrial membrane) that is up to 10 m in diameter and emerges from the OMM during infection with the human parasite Toxoplasma gondii. SPOTs are distinct from mitochondria-derived vesicles and compartments, and mediate the depletion of the OMM proteins MFN1 and MFN2 that restrict parasite growth. The formation of SPOTs depends on the parasite effector protein TgMAF1 and the host mitochondrial import receptor TOM70, which is required for optimal parasite proliferation. TOM70 enables TgMAF1 to interact with host SAM50, a major translocase of the OMM, and SAM50 inhibition or acute mitochondrial import stress are sufficient to promote SPOT formation independently of infection. We propose that Toxoplasma exploits SPOTs, a cellular response to OMM import stress, to promote its growth.

2022-08-04 | PXD024491 | Pride

ZFP423 Controls EBF2 Co-activator Recruitment and PPARgamma Occupancy to Determine the Thermogenic Plasticity of Adipocytes_ChIP-seq

Project description:Energy-storing white adipocytes maintain their identity by suppressing the gene program defining energy-burning thermogenic brown/beige adipocytes. Here, we reveal that the protein-protein interaction between the transcriptional co-regulator ZFP423 and brown/beige cell determination factor, EBF2, is essential for restraining the thermogenic phenotype of white adipose tissue (WAT). Disruption of the ZFP423-EBF2 protein interaction through CRISPR-Cas9 gene editing triggers widespread “browning” of WAT in adult mice. Mechanistically, adipocyte Zfp423 deficiency induces an EBF2 NuRD-to-BAF co-regulator switch and a shift in PPARgamma occupancy to thermogenic genes. This shift in PPARgamma occupancy increases the anti-diabetic efficacy of the PPARgamma agonist rosiglitazone in obesity while diminishing the unwanted weight-gaining effect of the drug. These data indicate that ZFP423 controls EBF2 co-activator recruitment and PPARgamma occupancy to determine the thermogenic plasticity of adipocytes and raise the concept of targeting transcriptional brakes in adipocyte gene expression as a therapeutic strategy to induce thermogenic adipocyte biogenesis in obesity.

2022-05-01 | GSE175654 | GEO

ZFP423 Controls EBF2 Co-activator Recruitment and PPARgamma Occupancy to Determine the Thermogenic Plasticity of Adipocytes_ChAP-seq

2022-05-01 | GSE175653 | GEO

Expression data from the subclones of Lewis Lung Carcinoma (LLC) cells

Project description:Medium conditioned by LLC cells stimulates thermogenic gene expression when added onto primary adipocytes. We generated single cell colonies from parental LLC cells. Media conditioned by the subclones stimulated thermogenic gene expression in primary adipocytes at varying degrees. Subclones 2, 3, 6 and 28 produce significantly larger amount of thermogenic activity than the subclones 18, 19, 23 and 24. We compared gene expression profiles of these subclones to identify secreted factors enriched in the more thermogenic clones. LLC subclones were cultured under conditioned medium preparation conditiones and total RNA was extracted from biological replicates.

2014-07-13 | E-GEOD-57797 | biostudies-arrayexpress

The obesity-linked human lncRNA AATBC regulates adipocyte plasticity by stimulating mitochondrial dynamics and respiration [II]

Project description:Adipocytes are critical regulators of metabolism and energy balance. While white adipocyte dysfunction is a hallmark of obesity-associated disorders, the activation of thermogenic brown and beige adipocytes is linked to improved cardiometabolic health. As adipocytes dynamically adapt to environmental cues by functionally switching between white and thermogenic phenotypes, a molecular understanding of this adipocyte plasticity could help improving energy balance and weight loss. Here, we show that the long non-coding RNA (lncRNA) Apoptosis associated transcript in bladder cancer (AATBC) is a human-specific regulator of adipocyte plasticity. Searching for new human lncRNAs implicated in adipocyte biology we compared transcriptional profiles of human adipose tissues and cultured adipocytes and discovered that AATBC was enriched in thermogenic conditions. Using primary human adipocytes and immortalized human adipocytes we found that gain-of-function of AATBC enhanced the thermogenic phenotype whereas loss-of-function diminished this effect. The AATBC-mediated increase in mitochondrial respiration was linked to a more fragmented mitochondrial network and vice versa. While we found that AATBC is predominantly located in the nucleus, its effect on global transcription was only marginal. As AATBC is specific to humans, we expressed AATBC in adipose tissue of mice to study its systemic impact, which led to lower plasma leptin levels. Interestingly, this association was also present in human subjects, as AATBC in adipose tissue was inversely correlated with plasma leptin levels, body mass index and other measures of metabolic health. In conclusion, AATBC is a novel obesity-linked regulator of adipocyte plasticity and mitochondrial function in humans.

2023-08-29 | GSE239671 | GEO

The obesity-linked human lncRNA AATBC regulates adipocyte plasticity by stimulating mitochondrial dynamics and respiration [1]

2023-08-29 | GSE236966 | GEO

Adipose tissue from β-3 agonist-treated mice

Project description:We previously established the transcription factor Zfp423 is critical for maintaining white adipocyte identity through suppression of the thermogenic gene program. The loss of Zfp423 in mature adipocytes triggers the rapid conversion of energy-storing white adipocytes into thermogenic beige adipocytes in subcutaneous WAT. In contrast to subcutaneous WAT, visceral WAT is relatively resistant to browning. However, visceral adipocytes lacing Zfp423 are capable of inducing the thermogenic gene program upon β-3 adrenergic stimulus. Here, we generated mice lacking Zfp423 in visceral adipose by breeding transgenic mice expressing Cre recombinase under the control of the Wilms Tumor 1 locus (Wt1-Cre) to animals carrying the floxed Zfp423 alleles (Zfp423loxP/loxP) (“Vis-KO” mice). Inactivation of Zfp423 in visceral WAT gives rise to thermogenic adipocytes that share properties of subcutaneous beige adipocytes and classic brown adipocytes.

2017-04-25 | GSE98132 | GEO

Differential junction usage in paired RNA-seq of white and beige differentiated adipocytes from six human subjects

Project description:Background: The beneficial effect of thermogenic adipocytes in maintaining body weight and protecting against metabolic disorders has raised interest in understanding the regulatory mechanisms defining white and beige adipocyte identity. Although alternative splicing has been shown to propagate adipose browning signals in mice, this has yet to be thoroughly investigated in human adipocytes. Methods: We performed parallel white and beige adipogenic differentiation using primary adipose stem cells from 6 unrelated healthy subjects, and assessed differential gene and isoform expression in mature adipocytes by RNA sequencing. Results: We find 693 exon junctions with robust differential usage between white and beige adipocytes in all 6 subjects, mapping to 507 genes. Importantly, only 8% of these differentially spliced genes are also differentially expressed, indicating that alternative splicing constitutes an additional layer of gene expression regulation during beige adipocyte adipogenic differentiation. Functional classification of alternative isoforms point to a gain of function for key thermogenic regulators such as PPARG, CITED1 and PEMT. We find that a large majority of the splice variants arise from differential usage of transcription start sites (TSSs), with beige-specific TSSs being enriched for PPARγ and MED1 binding compared to white-specific TSSs. Finally, we validate beige specific isoform expression at the protein level for two thermogenic regulators, PPARγ and PEMT. Discussion: These results indicate that differential isoform expression through alternative TSS usage is an important regulatory mechanism for human adipocyte thermogenic specification. Code for data processing and analysis are available at https://github.com/sarahhp/splicing_thermogenesis.

2024-05-14 | GSE256259 | GEO