Large-scale chemical dissection of mitochondrial function.
Mitochondrial oxidative phosphorylation (OXPHOS) is under the control of both mitochondrial (mtDNA) and nuclear genomes and is central to energy homeostasis. To investigate how its function and regulation are integrated within cells, we systematically combined four cell-based assays of OXPHOS physiology with multiplexed measurements of nuclear and mtDNA gene expression across 2,490 small-molecule perturbations in cultured muscle. Mining the resulting compendium revealed, first, that protein synthesis inhibitors can decouple coordination of nuclear and mtDNA transcription; second, that a subset of HMG-CoA reductase inhibitors, combined with propranolol, can cause mitochondrial toxicity, yielding potential clues about the etiology of statin myopathy; and, third, that structurally diverse microtubule inhibitors stimulate OXPHOS transcription while suppressing reactive oxygen species, via a transcriptional mechanism involving PGC-1alpha and ERRalpha, and thus may be useful in treating age-associated degenerative disorders. Our screening compendium can be used as a discovery tool both for understanding mitochondrial biology and toxicity and for identifying novel therapeutics.
Wagner
Bridget K
BK
Broad Institute of Massachusetts Institute of Technology and Harvard, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.
Kitami
Toshimori
T
Gilbert
Tamara J
TJ
Peck
David
D
Ramanathan
Arvind
A
Schreiber
Stuart L
SL
Golub
Todd R
TR
Mootha
Vamsi K
VK
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics; D064420:Drug-Related Side Effects and Adverse Reactions; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D016678:Genome / Q000235:genetics; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D010085:Oxidative Phosphorylation / Q000187:drug effects; D004364:Pharmaceutical Preparations / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D050257:Tubulin Modulators / Q000494:pharmacology
D004272:DNA, Mitochondrial; D004364:Pharmaceutical Preparations; D017382:Reactive Oxygen Species; D050257:Tubulin Modulators