Large-scale chemical dissection of mitochondrial function

  • A Corrigendum to this article was published on 01 July 2008

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-1α and ERRα, 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.

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Figure 1: Complementary profiles of viability, mitochondrial physiology and gene expression across 2,490 chemical perturbations.
Figure 2: Coupling of nuclear and mitochondrial OXPHOS expression.
Figure 3: Statin-induced mitochondrial toxicity.
Figure 4: Two complementary strategies to identify small molecules that boost OXPHOS gene expression and decrease ROS levels.
Figure 5: Secondary analyses of the effects of microtubule inhibitors on OXPHOS gene expression and physiology.

Change history

  • 08 July 2008

    In the version of this article initially published, on p.348, column 2, paragraph 2, line 7, the following sentence was incorrect: “Statins block the synthesis of cholesterol—a precursor to ubiquinone….” It should have read “Statins block the synthesis of mevalonate, a precursor not only of cholesterol but also ubiquinone, ….” The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank Stephanie Norton, Jason Burbank, Mariah Eustice and Nicky Tolliday for assistance in high-throughput screening; Nathan Billings and Olga Goldberger for technical assistance; Oded Shaham, Ken Ross and Paul Clemons for computational assistance; and Joel Hirschhorn, Eric Lander and Robert Gould for thoughtful discussions and comments on the manuscript. S.L.S. and T.R.G. are Investigators of the Howard Hughes Medical Institute. V.K.M. is recipient of a Career Award in the Biomedical Sciences from the Burroughs Wellcome Fund, a Charles E. Culpeper Scholarship in Medical Science, and a Physician Scientist Early Career Award from the Howard Hughes Medical Institute. This work was supported by grants from the National Institute of Health (National Institute of Diabetes and Digestive and Kidney Diseases), the American Diabetes Association and the Richard and Susan Smith Family Foundation (V.K.M.).

Author information

V.K.M. conceived of and supervised the project. B.K.W., T.K. and V.K.M. designed the experiments and analyzed the data. T.J.G., A.R. and B.K.W. carried out phenotypic screening. D.P. and T.K. carried out GE-HTS experiments. S.L.S. and T.R.G. provided guidance on chemical screening and GE-HTS, respectively, and advised on analysis. B.K.W., T.K. and V.K.M. wrote the paper.

Correspondence to Vamsi K Mootha.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 and Supplementary Table 4 (PDF 885 kb)

Supplementary Table 1

3120 compound instances, 2490 unique compounds. (XLS 1506 kb)

Supplementary Table 2

Rank CompoundName. (XLS 18 kb)

Supplementary Table 3

ClusterID. (XLS 33 kb)

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