Bromodomain Inhibitors Correct Bioenergetic Deficiency Caused by Mitochondrial Disease Complex I Mutations

Joeva J. Barrow, Eduardo Balsa, Francisco Verdeguer, Clint D J Tavares, Meghan S. Soustek, Louis R. Hollingsworth, Mark Jedrychowski, Rutger Vogel, Joao A. Paulo, Jan Smeitink, Steve P. Gygi, John Doench, David E. Root, Pere Puigserver

Research output: Contribution to journalArticle

Abstract

Mitochondrial diseases comprise a heterogeneous group of genetically inherited disorders that cause failures in energetic and metabolic function. Boosting residual oxidative phosphorylation (OXPHOS) activity can partially correct these failures. Herein, using a high-throughput chemical screen, we identified the bromodomain inhibitor I-BET 525762A as one of the top hits that increases COX5a protein levels in complex I (CI) mutant cybrid cells. In parallel, bromodomain-containing protein 4 (BRD4), a target of I-BET 525762A, was identified using a genome-wide CRISPR screen to search for genes whose loss of function rescues death of CI-impaired cybrids grown under conditions requiring OXPHOS activity for survival. We show that I-BET525762A or loss of BRD4 remodeled the mitochondrial proteome to increase the levels and activity of OXPHOS protein complexes, leading to rescue of the bioenergetic defects and cell death caused by mutations or chemical inhibition of CI. These studies show that BRD4 inhibition may have therapeutic implications for the treatment of mitochondrial diseases.

Original languageEnglish (US)
Pages (from-to)163-175
Number of pages13
JournalMolecular Cell
Volume64
Issue number1
DOIs
StatePublished - Oct 6 2016
Externally publishedYes

Keywords

  • BRD4
  • bromodomain inhibitors
  • mitochondria
  • mitochondrial disorders
  • OXPHOS
  • PGC-1α

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Barrow, J. J., Balsa, E., Verdeguer, F., Tavares, C. D. J., Soustek, M. S., Hollingsworth, L. R., Jedrychowski, M., Vogel, R., Paulo, J. A., Smeitink, J., Gygi, S. P., Doench, J., Root, D. E., & Puigserver, P. (2016). Bromodomain Inhibitors Correct Bioenergetic Deficiency Caused by Mitochondrial Disease Complex I Mutations. Molecular Cell, 64(1), 163-175. https://doi.org/10.1016/j.molcel.2016.08.023