Dataset Information

BRD4-mediated epigenetic regulation of endoplasmic reticulum-mitochondria contact sites is governed by the mitochondrial complex III

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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Joao Paulo

LAB HEAD: Joseph D. Mancias, MD, PhD

PROVIDER: PXD056917 | Pride | 2026-06-08

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	az03661.raw	Raw
	az036612024_0724_Shah_Mitosamples_2024_0724_Shah_Mitosamples_.mzIdentML	Mzid
	xb12092.raw	Raw
	xb12092mito_wcl.mzIdentML	Mzid
	xb12093.raw	Raw

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Publications

BRD4-mediated ER membrane contact creates functionally distinct mitochondrial subtypes.

Chen Brandon B Stark Drew C DC Jadhav Pankaj V PV Lynn-Nguyen Theophilus M TM Halligan Benjamin S BS Rossiter Nicholas J NJ Sindoni Nicole N Shin Myungsun M Paulo Joao A JA Chang Matthew M Koo Imhoi I Koshkin Sergei S Eyunni Sanjana S Ronchi Paolo P Paulsen Michelle T MT Greenbaum Harrison S HS Ruckert Mariana T MT Morlacchi Pietro P Hanna David A DA Lin Jason J Guerra Rachel M RM Liu Tao T Pagliarini David J DJ Banerjee Ruma R Parolia Abhijit A Ljungman Mats E ME Patterson Andrew D AD Mancias Joseph D JD Mosalaganti Shyamal S Sexton Jonathan Z JZ Calì Tito T Lyssiotis Costas A CA Shah Yatrik M YM

Molecular cell 20260213 5

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 abun ...[more]

PMID: 41690300

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