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

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


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.

MeSH terms

  • Benzodiazepines / pharmacology*
  • Cell Cycle Proteins
  • Cell Fusion
  • Cell Line
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Cytochrome c Group / genetics*
  • Cytochrome c Group / metabolism
  • Electron Transport Complex I / deficiency
  • Electron Transport Complex I / genetics*
  • Electron Transport Complex IV
  • Gene Expression Profiling
  • Gene Expression Regulation
  • High-Throughput Screening Assays
  • Humans
  • Metabolome
  • Metabolomics
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Mitochondrial Diseases / drug therapy
  • Mitochondrial Diseases / genetics
  • Mitochondrial Diseases / metabolism
  • Mitochondrial Diseases / pathology
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Oxidative Phosphorylation / drug effects
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Promoter Regions, Genetic
  • Protein Binding
  • Signal Transduction
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism


  • BRD4 protein, human
  • Cell Cycle Proteins
  • Cytochrome c Group
  • Mitochondrial Proteins
  • Nuclear Proteins
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Transcription Factors
  • Benzodiazepines
  • molibresib
  • COX5A protein, human
  • Electron Transport Complex IV
  • Electron Transport Complex I