BRD4-mediated ER membrane contact creates functionally distinct mitochondrial subtypes

Brandon Chen; Drew C Stark; Pankaj V Jadhav; Theophilus M Lynn-Nguyen; Benjamin S Halligan; Nicholas J Rossiter; Nicole Sindoni; Myungsun Shin; Joao A Paulo; Matthew Chang; Imhoi Koo; Sergei Koshkin; Sanjana Eyunni; Paolo Ronchi; Michelle T Paulsen; Harrison S Greenbaum; Mariana T Ruckert; Pietro Morlacchi; David A Hanna; Jason Lin; Rachel M Guerra; Tao Liu; David J Pagliarini; Ruma Banerjee; Abhijit Parolia; Mats E Ljungman; Andrew D Patterson; Joseph D Mancias; Shyamal Mosalaganti; Jonathan Z Sexton; Tito Calì; Costas A Lyssiotis; Yatrik M Shah

doi:10.1016/j.molcel.2026.01.012

BRD4-mediated ER membrane contact creates functionally distinct mitochondrial subtypes

Mol Cell. 2026 Mar 5;86(5):917-936.e12. doi: 10.1016/j.molcel.2026.01.012. Epub 2026 Feb 13.

Authors

Brandon Chen¹, Drew C Stark², Pankaj V Jadhav³, Theophilus M Lynn-Nguyen⁴, Benjamin S Halligan⁵, Nicholas J Rossiter¹, Nicole Sindoni⁶, Myungsun Shin⁷, Joao A Paulo⁸, Matthew Chang³, Imhoi Koo⁹, Sergei Koshkin¹⁰, Sanjana Eyunni¹¹, Paolo Ronchi¹², Michelle T Paulsen¹³, Harrison S Greenbaum¹, Mariana T Ruckert¹⁴, Pietro Morlacchi¹⁵, David A Hanna¹⁶, Jason Lin¹⁴, Rachel M Guerra¹⁷, Tao Liu¹⁴, David J Pagliarini¹⁸, Ruma Banerjee¹⁶, Abhijit Parolia¹⁹, Mats E Ljungman²⁰, Andrew D Patterson⁹, Joseph D Mancias⁶, Shyamal Mosalaganti²¹, Jonathan Z Sexton²², Tito Calì²³, Costas A Lyssiotis²⁴, Yatrik M Shah²⁵

Affiliations

¹ Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
² Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Cancer Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
³ Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, United States.
⁴ Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109, USA; College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109, USA.
⁶ Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁷ Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
⁸ Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
⁹ Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, State College, PA, USA.
¹⁰ Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, State College, PA, USA.
¹¹ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Molecular and Cellular Pathology Program, University of Michigan, Ann Arbor, MI 48109, USA.
¹² Electron Microscopy Core Facility, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
¹³ Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁴ Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁵ Agilent Technologies, Inc., Lexington, MA 02421, USA.
¹⁶ Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
¹⁷ Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹⁸ Departament of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Howard Hughes Medical Institute, St. Louis, MO 63110, USA.
¹⁹ Cancer Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA.
²⁰ Cancer Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
²¹ Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, United States; Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Biophysics, College of Literature, Science and the Arts, University of Michigan, Ann Arbor, MI 48109, USA.
²² Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109, USA; College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA; Center for Drug Repurposing, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Institute for Clinical and Health Research, University of Michigan, Ann Arbor, MI 48109, USA.
²³ Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; Padova Neuroscience Center (PNC), University of Padova, 35131 Padova, Italy; Center for Neurodegenerative Disease Research (CESNE), University of Padova, 35131 Padova, Italy.
²⁴ Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Cancer Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. Electronic address: clyssiot@umich.edu.
²⁵ Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Cancer Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. Electronic address: shahy@umich.edu.

PMID: 41690300
DOI: 10.1016/j.molcel.2026.01.012

Abstract

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.

Keywords: bromodomain protein; endoplasmic reticulum-mitochondria contact sites; high-throughput screening; mitochondrial electron transport chain.

MeSH terms

Animals
Bromodomain Containing Proteins
Cell Cycle Proteins* / genetics
Cell Cycle Proteins* / metabolism
Endoplasmic Reticulum* / drug effects
Endoplasmic Reticulum* / genetics
Endoplasmic Reticulum* / metabolism
Endoplasmic Reticulum* / ultrastructure
Epigenesis, Genetic / drug effects
Humans
Mitochondria* / drug effects
Mitochondria* / genetics
Mitochondria* / metabolism
Mitochondria* / ultrastructure
Nuclear Proteins* / genetics
Nuclear Proteins* / metabolism
Signal Transduction / drug effects
Transcription Factors* / genetics
Transcription Factors* / metabolism

Substances

Transcription Factors
BRD4 protein, human
Cell Cycle Proteins
Nuclear Proteins
Bromodomain Containing Proteins

Abstract

MeSH terms

Substances

Grants and funding