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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $20.83 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Anderson, S. et al. Sequence and organization of the human mitochondrial genome. Nature 290, 457–465 (1981).
Chance, B. & Williams, G.R. Respiratory enzymes in oxidative phosphorylation. III. The steady state. J. Biol. Chem. 217, 409–427 (1955).
DiMauro, S. & Schon, E.A. Mitochondrial respiratory-chain diseases. N. Engl. J. Med. 348, 2656–2668 (2003).
Mootha, V.K. et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003).
Petersen, K.F. et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300, 1140–1142 (2003).
Balaban, R.S., Nemoto, S. & Finkel, T. Mitochondria, oxidants, and aging. Cell 120, 483–495 (2005).
Kelly, D.P. & Scarpulla, R.C. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev. 18, 357–368 (2004).
Weinstein, J.N. et al. An information-intensive approach to the molecular pharmacology of cancer. Science 275, 343–349 (1997).
Hughes, T.R. et al. Functional discovery via a compendium of expression profiles. Cell 102, 109–126 (2000).
Lamb, J. et al. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313, 1929–1935 (2006).
Ramanathan, A., Wang, C. & Schreiber, S.L. Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements. Proc. Natl. Acad. Sci. USA 102, 5992–5997 (2005).
Leary, S.C., Battersby, B.J., Hansford, R.G. & Moyes, C.D. Interactions between bioenergetics and mitochondrial biogenesis. Biochim. Biophys. Acta 1365, 522–530 (1998).
Dolma, S., Lessnick, S.L., Hahn, W.C. & Stockwell, B.R. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 3, 285–296 (2003).
Smiley, S.T. et al. Intracellular heterogeneity in mitochondrial membrane potentials revealed by a J-aggregate-forming lipophilic cation JC-1. Proc. Natl. Acad. Sci. USA 88, 3671–3675 (1991).
Berridge, M.V. & Tan, A.S. Characterization of the cellular reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT): subcellular localization, substrate dependence, and involvement of mitochondrial electron transport in MTT reduction. Arch. Biochem. Biophys. 303, 474–482 (1993).
Crouch, S.P., Kozlowski, R., Slater, K.J. & Fletcher, J. The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity. J. Immunol. Methods 160, 81–88 (1993).
Ye, G., Metreveli, N.S., Ren, J. & Epstein, P.N. Metallothionein prevents diabetes-induced deficits in cardiomyocytes by inhibiting reactive oxygen species production. Diabetes 52, 777–783 (2003).
Stegmaier, K. et al. Gene expression–based high-throughput screening (GE-HTS) and application to leukemia differentiation. Nat. Genet. 36, 257–263 (2004).
Peck, D. et al. A method for high-throughput gene expression signature analysis. Genome Biol. 7, R61 (2006).
Kim, Y.K. et al. Relationship of stereochemical and skeletal diversity of small molecules to cellular measurement space. J. Am. Chem. Soc. 126, 14740–14745 (2004).
Franz, A.K., Dreyfuss, P.D. & Schreiber, S.L. Synthesis and cellular profiling of diverse organosilicon small molecules. J. Am. Chem. Soc. 129, 1020–1021 (2007).
Larsson, N.G. & Clayton, D.A. Molecular genetic aspects of human mitochondrial disorders. Annu. Rev. Genet. 29, 151–178 (1995).
Clayton, D.A. Transcription of the mammalian mitochondrial genome. Annu. Rev. Biochem. 53, 573–594 (1984).
Antonetti, D.A., Reynet, C. & Kahn, C.R. Increased expression of mitochondrial-encoded genes in skeletal muscle of humans with diabetes mellitus. J. Clin. Invest. 95, 1383–1388 (1995).
Huang, X. et al. Insulin-regulated mitochondrial gene expression is associated with glucose flux in human skeletal muscle. Diabetes 48, 1508–1514 (1999).
Heddi, A., Stepien, G., Benke, P.J. & Wallace, D.C. Coordinate induction of energy gene expression in tissues of mitochondrial disease patients. J. Biol. Chem. 274, 22968–22976 (1999).
Graham, D.J. et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. J. Am. Med. Assoc. 292, 2585–2590 (2004).
Dirks, A.J. & Jones, K.M. Statin-induced apoptosis and skeletal myopathy. Am. J. Physiol. 291, C1208–C1212 (2006).
van Vliet, A.K., Negre-Aminou, P., van Thiel, G.C., Bolhuis, P.A. & Cohen, L.H. Action of lovastatin, simvastatin, and pravastatin on sterol synthesis and their antiproliferative effect in cultured myoblasts from human striated muscle. Biochem. Pharmacol. 52, 1387–1392 (1996).
Frendin, T.J. & Swainson, C.P. Acute renal failure secondary to non-traumatic rhabdomyolysis following amoxapine overdose. N. Z. Med. J. 98, 690–691 (1985).
Blessing, W. & Walsh, J.C. Myotonia precipitated by propranolol therapy. Lancet 309, 73–74 (1977).
Davidson, B.K. Myositis associated with griseofulvin therapy. Am. Fam. Physician 52, 1277 (1995).
Delobel, P. & Pradinaud, R. Rhabdomyolysis associated with pentamidine isethionate therapy for American cutaneous leishmaniasis. J. Antimicrob. Chemother. 51, 1319–1320 (2003).
Rowinsky, E.K. et al. Phase I and pharmacologic study of paclitaxel and cisplatin with granulocyte colony-stimulating factor: neuromuscular toxicity is dose-limiting. J. Clin. Oncol. 11, 2010–2020 (1993).
Aronson, J.K. Ed. Meyler's Side Effects of Drugs 15th edn. (Elsevier Science, Burlington, Massachusetts, USA, 2006).
Bliss, C.I. The toxicity of poisons applied jointly. Ann. Appl. Biol. 26, 585–615 (1939).
Kelley, D.E., He, J., Menshikova, E.V. & Ritov, V.B. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51, 2944–2950 (2002).
Houstis, N., Rosen, E.D. & Lander, E.S. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440, 944–948 (2006).
Lustbader, J.W. et al. ABAD directly links Aβ to mitochondrial toxicity in Alzheimer's disease. Science 304, 448–452 (2004).
Li, W.L., Zheng, H.C., Bukuru, J. & De Kimpe, N. Natural medicines used in the traditional Chinese medical system for therapy of diabetes mellitus. J. Ethnopharmacol. 92, 1–21 (2004).
Bonawitz, N.D., Clayton, D.A. & Shadel, G.S. Initiation and beyond: multiple functions of the human mitochondrial transcription machinery. Mol. Cell 24, 813–825 (2006).
Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115–124 (1999).
Mootha, V.K. et al. Errα and Gabpa/b specify PGC-1α-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc. Natl. Acad. Sci. USA 101, 6570–6575 (2004).
Valle, I., Alvarez-Barrientos, A., Arza, E., Lamas, S. & Monsalve, M. PGC-1alpha regulates the mitochondrial antioxidant defense system in vascular endothelial cells. Cardiovasc. Res. 66, 562–573 (2005).
Freyssenet, D., Irrcher, I., Connor, M.K., DiCarlo, M. & Hood, D.A. Calcium-regulated changes in mitochondrial phenotype in skeletal muscle cells. Am. J. Phys. 286, 1053–1061 (2004).
Caprio, S. et al. Improvement of metabolic control in diabetic patients during mebendazole administration: preliminary studies. Diabetologia 27, 52–55 (1984).
Karbowski, M. et al. Opposite effects of microtubule-stabilizing and microtubule-destabilizing drugs on biogenesis of mitochondria in mammalian cells. J. Cell Sci. 114, 281–291 (2001).
Mitchell, P. Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature 199, 144–148 (1961).
Lee, P.D., Sladek, R., Greenwood, C.M. & Hudson, T.J. Control genes and variability: absence of ubiquitous reference transcripts in diverse mammalian expression studies. Genome Res. 12, 292–297 (2002).
Hieronymus, H. et al. Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell 10, 321–330 (2006).
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.).
About this article
Annual Review of Analytical Chemistry (2019)
Niclosamide activates the NLRP3 inflammasome by intracellular acidification and mitochondrial inhibition
Communications Biology (2019)
Dynamical evidence for causality between Northern Hemisphere annular mode and winter surface air temperature over Northeast Asia
Climate Dynamics (2019)