Research abstract
Resources abstract
Nature Biotechnology 26, 343 - 351 (2008)
Published online: 24 February 2008 | Corrected online: 8 July 2008 | doi:10.1038/nbt1387
There is a Corrigendum (July 2008) associated with this Resources.
Large-scale chemical dissection of mitochondrial function
Bridget K Wagner1,5, Toshimori Kitami1,2,5, Tamara J Gilbert1, David Peck1, Arvind Ramanathan1, Stuart L Schreiber1, Todd R Golub1,3 & Vamsi K Mootha1,2,4
Abstract
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-1
and ERR, 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.
- Broad Institute of Massachusetts Institute of Technology and Harvard, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.
- Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.
- Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02446, USA.
- These authors contributed equally to this work.
Correspondence to: Vamsi K Mootha1,2,4 e-mail: vamsi@hms.harvard.edu
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