Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

BRD4-mediated ER membrane contact creates functionally distinct mitochondrial subtypes

ABSTRACT: Inter-organellar communication is critical for cellular metabolic homeostasis. One of the most abundant inter-organellar interactions are those at the endoplasmic reticulum and mitochondria contact sites (ERMCS). However, a detailed understanding of the mechanisms governing ERMCS regulation and their roles in cellular metabolism are limited by a lack of tools that permit temporal induction and reversal. Through unbiased screening approaches, we identified fedratinib, an FDA-approved drug, that dramatically increases ERMCS abundance by inhibiting the epigenetic modifier BRD4. Fedratinib rapidly and reversibly modulates mitochondrial and ER morphology and alters metabolic homeostasis. Moreover, ERMCS modulation depends on mitochondria electron transport chain complex III function. Comparison of fedratinib activity to other reported inducers of ERMCS revealed common mechanisms of induction and function, providing clarity and union to a growing body of experimental observations. In total, our results uncovered a novel epigenetic signaling pathway and an endogenous metabolic regulator that connects ERMCS and cellular metabolism.

ORGANISM(S): Homo sapiens

PROVIDER: GSE278077 | GEO | 2026/03/24

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

BRD4-mediated ER membrane contact creates functionally distinct mitochondrial subtypes

Project description:Inter-organellar communication is critical for cellular metabolism. One of the most abundant inter-organellar interactions occurs at the endoplasmic reticulum and mitochondria contact sites (ERMCSs). However, an understanding of the mechanisms governing ERMCS regulation and their roles in cellular metabolism is limited by a lack of tools that permit temporal induction and reversal. Through screening approaches, we identified fedratinib, an FDA-approved drug that dramatically increases ERMCS abundance by inhibiting the epigenetic modifier BRD4. Fedratinib rapidly and reversibly modulates mitochondrial and ER morphology, induces a distinct ER-mitochondria envelopment structure, and alters metabolic homeostasis. Moreover, ERMCS modulation depends on mitochondrial electron transport chain complex III function. Comparison of fedratinib activity to other reported inducers of ERMCSs revealed common mechanisms of induction and function, providing clarity to a growing body of experimental observations. In total, our results uncovered a novel epigenetic signaling pathway and an endogenous metabolic regulator that connects ERMCSs and cellular metabolism.

2026-03-25 | GSE280900 | GEO

LipoID: a Photochemical Proteomic Approach to in situ Profile Lipid Droplets Interactions and Identify Inter-Organelle Regulators

Project description:Lipid droplets (LDs) dynamically interact with other organelles, such as mitochondria, in surveillance of cellular metabolic homeostasis. The transient nature of LDs, however, poses technical challenges to snapshot molecular information underlying these interactions. Herein, we develop a small molecule based photocatalytic protein proximity labeling method (namely LipoID) to in situ label, capture and profile LDs’ interacting proteome. This method is enabled by a set of LDs-targeting probes designed to catalyze protein modifications nearby LDs using nucleophilic substrates. Profiled by LC-MS/MS, LipoID identifies tethered inter-organellar interactions, particularly with mitochondria, besides reliable capture of validated LDs’ biomarkers (e.g. PLINs). Coupled with comparative proteomics, LipoID discovers mitochondrial VDAC3 channel and its inhibitor that regulate the LDs-mitochondria distance. Such inter-organellar regulation was driven by cellular ATP transported through the VDAC3 channel. Further metabolomics analysis revealed remodeled lipid metabolism orchestrated with LDs-mitochondria interaction. Together, LipoID profiles LDs’ interactome and reveals inter-organellar regulation.

| PXD063703 |

Mitochondria-Rough-ER Contacts in The Liver Regulate Systemic Lipid Homeostasis

Project description:Contacts between organelles create microdomains that play major roles in regulating key intracellular activities and signaling pathways, but whether they also regulate systemic functions remains unknown. Here, we report the ultrastructural organization and dynamics of the inter-organellar contact established by rough-Endoplasmic Reticulum closely wrapped around the mitochondria (wrappER). To elucidate the in vivo function of this contact, mouse liver fractions enriched in wrappER-associated-mitochondria are analyzed by transcriptomics, proteomics and lipidomics. The biochemical signature of the wrappER points to a role in the biogenesis of very-low-density lipoproteins (VLDL). Altering wrappER-mitochondria contacts curtails VLDL secretion and increases hepatic fatty acids, lipid droplets and neutral lipid content. Conversely, acute liver-specific ablation of Mttp, the most upstream regulator of VLDL biogenesis, recapitulates this hepatic dyslipidemia phenotype and promotes remodelling of the wrappER-mitochondria contact. The discovery that liver wrappER-mitochondria contacts participate in VLDL biology suggests an involvement of inter-organelle contacts in systemic lipid homeostasis.

2021-03-15 | GSE134777 | GEO

LipoID: a Photochemical Proteomic Method to in situ Profile Lipid Droplet Interactions and Identify Regulating Factors

Project description:In surveillance of cellular energy homeostasis, lipid droplets (LDs) dynamically interact with other organelles, such as mitochondria, to tightly engage in metabolic regulations. The transient nature of LDs’ interactions, however, poses technical challenges to snapshot the enriched information by classical fractionation methods. Herein, we develop a small molecule based photocatalytic protein proximity labeling method (namely LipoID) to in situ label, capture and profile LDs’ interacting proteome in live cells. To this end, a set of LD-targeting probes are designed to undergo photocatalytic protein modifications in close proximity to LDs by nucleophilic substrates. Photochemical mechanistic studies confirm predominant modification on histidine residues via type I radical pathway. We show the LipoID method identifies inter-organellar interactions, particularly with mitochondria, besides reliable capture of validated LDs’ biomarkers (e.g. Plins). We also exemplify LipoID coupled with comparative proteomic analysis discovers key mitochondrial channel VDAC3 to regulate the inter-organellar distance between LDs and mitochondria. Together, the small molecule based LipoID method reported herein allows us to in situ and de novo study LD interactions without genetic-encoding a functional tag to a known biomarker.

| PXD055727 |

Atf-6 regulates lifespan through ER-mitochondrial calcium homeostasis

Project description:Functional crosstalk between organelles is critical for maintaining cellular homeostasis. Individually, dysfunction of both endoplasmic reticulum (ER) and mitochondria have been linked to cellular and organismal aging, but little is known about how mechanisms of inter-organelle communication might be targeted to extended longevity. The metazoan unfolded protein response (UPR) maintains ER health through a variety of mechanisms beyond its canonical role in proteostasis, including calcium storage and lipid metabolism. Here we provide evidence that in C. elegans, inhibition of the conserved UPR mediator, activating transcription factor (atf)-6 increases lifespan via modulation of calcium homeostasis and signaling to the mitochondria. Loss of atf-6 confers long life via downregulation of the ER calcium buffering protein, calreticulin. Function of the ER calcium release channel, the inositol triphosphate receptor (IP3R/itr-1), is required for atf-6 mutant longevity while a gain-of-function IP3R/itr-1 mutation is sufficient to extend lifespan. IP3R dysfunction leads to altered mitochondrial behavior and hyperfused morphology, which is sufficient to suppress long life in atf-6 mutants. Highlighting a novel and direct role for this inter-organelle coordination of calcium in longevity, the mitochondrial calcium import channel, mcu-1, is also required for atf-6 mutant longevity. Altogether this study reveals the importance of organellar coordination of calcium handling in determining the quality of aging, and highlights calcium homeostasis as a critical output for the UPR and atf-6 in particular.

2020-08-12 | GSE156037 | GEO

Mapping the castor bean endosperm proteome revealed a metabolic interaction between plastid, mitochondria, and peroxisomes to optimize seedling growth

Project description:The aim of the project was to elucidate the inter-organellar interplay of plastids, mitochondria, and peroxisomes during storage reserve mobilization in the endosperm to supply the growing seedling with nutrients upon germination. Organelles from endosperm of etiolated castor bean seedlings were isolated and subjected to liquid chromatography-tandem mass spectrometry. The data were used to build a comprehensive metabolic model for plastids, mitochondria, and peroxisomes.

2024-01-09 | PXD040932 | Pride

Inter-organellar communication by a mitochondrial tRNA regulates nuclear metabolic transcription

Project description:Inter-organellar communication by a mitochondrial tRNA regulates nuclear metabolic transcription

| PRJNA879437 | ENA

Yeast Mitochondrial Derived Vesicles (MDVs) have membrane potential and contain a functional ATP synthase

Project description:Mitochondria are responsible for the production of energy and for essential metabolic pathways in the cell, as well as fundamental processes such as apoptosis and aging. Interestingly, while the import machinery of proteins into mitochondria is thoroughly understood, there is currently no known protein export mechanism from mitochondria. Vesicular transport is a means of inter-organellar communication, and in fact cells release vesicles in order to shuttle lipids, proteins, RNA and DNA between one another. Here we show for the first time that functional mitochondria, isolated from Saccharomyces cerevisiae can release vesicles, independent of the fission machinery. Mitochondrial secreted vesicles are relatively uniform in size, of about 100nm and carry a selection of cargo; only certain proteins are carried by these vesicles, of which some are matrix soluble and some are membrane proteins. We further demonstrate that yeast MDVs harbor a membrane potential, a functional ATP synthase complex, produce ATP, and fuse with naïve mitochondria. We suggest, that MDVs may have a function in organellar protein export, ATP production ability of damaged mitochondria and organelle-communication.

2023-01-29 | PXD035192 | Pride

Yeast Mitochondrial Derived Vesicles (MDVs) have membrane potential and contain a functional ATP synthase-Part 2

2023-01-29 | PXD039191 | Pride

Lipid biosynthesis coordinates a Mitochondrial to Cytosolic Stress Response

Project description:Defects in mitochondrial metabolism have been increasingly linked with age-onset protein misfolding diseases such as Alzheimerâs, Parkinsonâs, and Huntingtonâs. In response to protein folding stress, compartment-specific unfolded protein responses (UPRs) within the endoplasmic reticulum, mitochondria, and cytosol work in parallel to ensure cellular protein homeostasis. While perturbation of individual compartments can make other compartments more susceptible to protein stress, the cellular conditions that trigger cross-communication between the individual UPRs remain poorly understood. We have uncovered a conserved, robust mechanism linking mitochondrial protein homeostasis and the cytosolic folding environment through changes in lipid homeostasis. Metabolic restructuring caused by mitochondrial stress or small molecule activators trigger changes in gene expression coordinated uniquely by both the mitochondrial and cytosolic UPRs, protecting the cell from disease-associated proteins. Our data suggest an intricate and unique system of communication between UPRs in response to metabolic changes that could unveil new targets for diseases of protein misfolding. Because the induction of the MCSR due to hsp-6 RNAi required both hsf-1 and dve-1, key transcription factors required for the HSR and UPRmt, respectively, we asked which gene sets are coordinately regulated by both factors. We performed microarray analyses to determine which genes have their expression altered by hsp-6 RNAi and whether these genes are regulated either by hsf-1, dve-1 or both

2016-09-08 | E-GEOD-83722 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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