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Bromodomain inhibitors correct bioenergetic deficiency caused by mitochondrial disease complex I mutations


Barrow, Joeva J; Balsa, Eduardo; Verdeguer, Francisco; Tavares, Clint D J; Soustek, Meghan S; Hollingsworth, Louis R; Jedrychowski, Mark; Vogel, Rutger; Paulo, Joao A; Smeitink, Jan; Gygi, Steve P; Doench, John; Root, David E; Puigserver, Pere (2016). Bromodomain inhibitors correct bioenergetic deficiency caused by mitochondrial disease complex I mutations. Molecular Cell, 64(1):163-175.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Department of Molecular Mechanisms of Disease
07 Faculty of Science > Department of Molecular Mechanisms of Disease
Dewey Decimal Classification:570 Life sciences; biology
Uncontrolled Keywords:BRD4; OXPHOS; PGC-1α; bromodomain inhibitors; mitochondria; mitochondrial disorders
Language:English
Date:2016
Deposited On:18 Aug 2017 16:02
Last Modified:18 Aug 2017 16:02
Publisher:Cell Press (Elsevier)
ISSN:1097-2765
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.molcel.2016.08.023
Official URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055448/
PubMed ID:27666594

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