BRD4-mediated ER membrane contact creates functionally distinct mitochondrial subtypes
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.
Authors
- Imhoi Koo (ORCID: https://orcid.org/0000-0002-5816-0627)
- Paolo Ronchi (ORCID: https://orcid.org/0000-0001-9010-533X)
- Jonathan Z. Sexton (ORCID: https://orcid.org/0000-0002-9244-5888)
- Nicholas J. Rossiter (ORCID: https://orcid.org/0000-0001-7333-1546)
- Mariana T. Ruckert (ORCID: https://orcid.org/0000-0002-8282-4454)
- David A. Hanna (ORCID: https://orcid.org/0000-0003-0726-8707)
- Sanjana Eyunni (ORCID: https://orcid.org/0009-0006-5101-6506)
- Michelle T. Paulsen (ORCID: https://orcid.org/0000-0002-8090-0118)
- Ruma Banerjee (ORCID: https://orcid.org/0000-0002-5921-4906)
- David J. Pagliarini (ORCID: https://orcid.org/0000-0002-0001-0087)
- Theophilus Nguyen (ORCID: https://orcid.org/0009-0009-9692-5836)
- Mats Ljungman (ORCID: https://orcid.org/0000-0003-1553-6695)
- С. В. Кошкин (ORCID: https://orcid.org/0000-0002-6220-8304)
- Pietro Morlacchi
- Harrison S. Greenbaum (ORCID: https://orcid.org/0000-0002-3518-9160)
- Joseph Douglas Mancias (ORCID: https://orcid.org/0000-0002-0692-3717)
- Benjamin Halligan (ORCID: https://orcid.org/0000-0002-7587-2597)
- Drew Stark (ORCID: https://orcid.org/0009-0006-3394-160X)
- Brandon Chen (ORCID: https://orcid.org/0000-0002-6319-2228)
- Pankaj Jadhav (ORCID: https://orcid.org/0000-0003-0028-8975)
- Nicole Sindoni
- Matthew Chang
- Tao Liu
- Yatrik M. Shah
- Andrew D. Patterson
- Abhijit Parolia
- Costas A. Lyssiotis
- Tito Calì
- Myungsun Shin
- Jason Lin
- Shyamal Mosalaganti
- Rachel M. Guerra
- Joao A. Paulo
Institutions
- Pennsylvania State University (US)
- Harvard University (US)
- Agilent Technologies (United States) (US)
- University of Padua (IT)
- Washington University in St. Louis (US)
- University of Michigan (US)
- Michigan Medicine (US)
- Dana-Farber Cancer Institute (US)
- Michigan Center for Translational Pathology (US)
- European Molecular Biology Laboratory (DE)
Publication Details
- Journal
- Molecular Cell
- Published
- 2026-02-13
- DOI
- https://doi.org/10.1016/j.molcel.2026.01.012
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.00