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Mol Cell DOI:10.1016/j.molcel.2016.08.023

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

Publication TypeJournal Article
Year of Publication2016
AuthorsBarrow, JJ, Balsa, E, Verdeguer, F, Tavares, CDJ, Soustek, MS, Hollingsworth, LR, Jedrychowski, M, Vogel, R, Paulo, JA, Smeitink, J, Gygi, SP, Doench, J, Root, DE, Puigserver, P
JournalMol Cell
Volume64
Issue1
Pages163-175
Date Published2016 Oct 06
ISSN1097-4164
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.

DOI10.1016/j.molcel.2016.08.023
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/27666594?dopt=Abstract

Alternate JournalMol. Cell
PubMed ID27666594
PubMed Central IDPMC5055448
Grant ListR01 DK081418 / DK / NIDDK NIH HHS / United States
R24 DK080261 / DK / NIDDK NIH HHS / United States