gsk525762a and Mitochondrial-Diseases

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.

Topics: Benzodiazepines; Cell Cycle Proteins; Cell Fusion; Cell Line; Clustered Regularly Interspaced Short Palindromic Repeats; Cytochrome c Group; Electron Transport Complex I; Electron Transport Complex IV; Gene Expression Profiling; Gene Expression Regulation; High-Throughput Screening Assays; Humans; Metabolome; Metabolomics; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Nuclear Proteins; Oxidative Phosphorylation; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Promoter Regions, Genetic; Protein Binding; Signal Transduction; Transcription Factors

In this issue of Molecular Cell, Barrow et al. (2016) use two complementary approaches-one an assessment of a chemical library, and the other a genome-wide CRISPR screen-that both identify bromodomain-containing protein 4 (Brd4) as a therapeutic target for mtDNA diseases affecting complex I.

Topics: Benzodiazepines; Cell Cycle Proteins; Cell Fusion; Cell Line; Cytochrome c Group; Electron Transport Complex I; Electron Transport Complex IV; Gene Expression Regulation; High-Throughput Screening Assays; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Nuclear Proteins; Oxidative Phosphorylation; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Promoter Regions, Genetic; Protein Binding; Signal Transduction; Transcription Factors