Bromodomain Inhibitors Correct Bioenergetic Deficiency Caused by Mitochondrial Disease Complex I Mutations.
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.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA 02215; Department of Cell Biology, Harvard Medical School, Boston, MA, USA 02215.
Joeva J
JJ
Barrow
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA 02215; Department of Cell Biology, Harvard Medical School, Boston, MA, USA 02215.
Eduardo
E
Balsa
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA 02215; Department of Cell Biology, Harvard Medical School, Boston, MA, USA 02215.
Francisco
F
Verdeguer
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA 02215; Department of Cell Biology, Harvard Medical School, Boston, MA, USA 02215.
Clint D J
CD
Tavares
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA 02215; Department of Cell Biology, Harvard Medical School, Boston, MA, USA 02215.
Meghan S
MS
Soustek
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA 02215.
Louis R
LR
Hollingsworth
Department of Cell Biology, Harvard Medical School, Boston, MA, USA 02215.
Mark
M
Jedrychowski
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA 02215; Department of Cell Biology, Harvard Medical School, Boston, MA, USA 02215; Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands.
Rutger
R
Vogel
Department of Cell Biology, Harvard Medical School, Boston, MA, USA 02215.
Joao A
JA
Paulo
Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands.
Jan
J
Smeitink
Department of Cell Biology, Harvard Medical School, Boston, MA, USA 02215.
Steve P
SP
Gygi
Broad Institute of MIT and Harvard, Cambridge, MA, USA 02142.
John
J
Doench
Broad Institute of MIT and Harvard, Cambridge, MA, USA 02142.
David E
DE
Root
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA 02215; Department of Cell Biology, Harvard Medical School, Boston, MA, USA 02215; Broad Institute of MIT and Harvard, Cambridge, MA, USA 02142. Electronic address: pere_puigserver@dfci.harvard.edu.
Pere
P
Puigserver
D001569:Benzodiazepines / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D002459:Cell Fusion; D002460:Cell Line; D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D003574:Cytochrome c Group / Q000235:genetics* / Q000378:metabolism; D042967:Electron Transport Complex I / Q000172:deficiency / Q000235:genetics*; D003576:Electron Transport Complex IV; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D057166:High-Throughput Screening Assays; D006801:Humans; D055442:Metabolome; D055432:Metabolomics; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
D001569:Benzodiazepines; D018797:Cell Cycle Proteins; D003574:Cytochrome c Group; D042967:Electron Transport Complex I; D003576:Electron Transport Complex IV; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C486497:PPARGC1A protein, human; C554645:molibresib; C576944:COX5A protein, human
BRD4; OXPHOS; PGC-1α; bromodomain inhibitors; mitochondria; mitochondrial disorders
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