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Mol Cell. 2016 Oct 6;64(1):163-175. doi: 10.1016/j.molcel.2016.08.023. Epub 2016 Sep 22.

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

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA 02215; Department of Cell Biology, Harvard Medical School, Boston, MA, USA 02215.
2
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA 02215.
3
Department of Cell Biology, Harvard Medical School, Boston, MA, USA 02215.
4
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA 02215; Department of Cell Biology, Harvard Medical School, Boston, MA, USA 02215; Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands.
5
Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands.
6
Broad Institute of MIT and Harvard, Cambridge, MA, USA 02142.
7
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA 02215; Department of Cell Biology, Harvard Medical School, Boston, MA, USA 02215; Broad Institute of MIT and Harvard, Cambridge, MA, USA 02142. Electronic address: pere_puigserver@dfci.harvard.edu.

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.

KEYWORDS:

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

PMID:
27666594
PMCID:
PMC5055448
DOI:
10.1016/j.molcel.2016.08.023
[Indexed for MEDLINE]
Free PMC Article

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