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

• Published in: Molecular cell Vol. 64; no. 1; pp. 163 - 175
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.10.2016
• Subjects: Benzodiazepines - pharmacology; BRD4; bromodomain inhibitors; cell death; Cell Fusion; Cell Line; Clustered Regularly Interspaced Short Palindromic Repeats; cybrids; Cytochrome c Group - genetics; Cytochrome c Group - metabolism; death; Electron Transport Complex I - deficiency; Electron Transport Complex I - genetics; Gene Expression Profiling; Gene Expression Regulation; genes; genetic disorders; High-Throughput Screening Assays; Humans; Metabolome; Metabolomics; mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial Diseases - drug therapy; Mitochondrial Diseases - genetics; Mitochondrial Diseases - metabolism; Mitochondrial Diseases - pathology; mitochondrial disorders; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; mutants; mutation; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; oxidative phosphorylation; Oxidative Phosphorylation - drug effects; OXPHOS; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; PGC-1α; Promoter Regions, Genetic; Protein Binding; proteome; Signal Transduction; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; OXPHOS; PGC-1α; bromodomain inhibitors; mitochondrial disorders; mitochondria; BRD4
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2016.08.023

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. [Display omitted] •Bromodomain inhibitors or BRD4 ablation boosts OXPHOS capacity in CI mutant cells•Inhibition of BRD4 rescues CI mutant cells from galactose-induced cell death•BRD4 binds to OXPHOS promoters and competes with PGC-1α binding•Bromodomain inhibition rewires the metabolome in CI mutant cells to preserve ATP Mitochondrial diseases cause failures in energetic function. Boosting oxidative phosphorylation (OXPHOS) activity can be therapeutic. Barrow et al. (2016) demonstrate through high-throughput chemical and CRISPR genetic screens that the protein BRD4 can be a therapeutic target. Inhibiting BRD4 increases OXPHOS capacity, rewires the metabolome, and rescues complex I mutant cells from death.