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Large-scale chemical dissection of mitochondrial function.

Publication TypeJournal Article
AuthorsWagner, BK, Kitami T., Gilbert TJ, Peck D., Ramanathan A., Schreiber SL, Golub T. R., and Mootha VK
AbstractMitochondrial 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.
Year of Publication2008
JournalNature biotechnology
Volume26
Issue3
Pages343-51
Date Published (YYYY/MM/DD)2008/03/01
ISSN Number1087-0156
DOI10.1038/nbt1387
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/18297058?dopt=Abstract