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Research ArticleArticle

The Biarylpyrazole Compound AM251 Alters Mitochondrial Physiology via Proteolytic Degradation of ERRα

Susan M. Krzysik-Walker, Isabel González-Mariscal, Morten Scheibye-Knudsen, Fred E. Indig and Michel Bernier
Molecular Pharmacology January 2013, 83 (1) 157-166; DOI: https://doi.org/10.1124/mol.112.082651
Susan M. Krzysik-Walker
Laboratory of Clinical Investigation (S.M.K.-W., I.G.-M., F.E.I., M.B.), Laboratory of Molecular Gerontology (M.S.-K.), National Institute on Aging, National Institutes of Health, Baltimore, Maryland
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Isabel González-Mariscal
Laboratory of Clinical Investigation (S.M.K.-W., I.G.-M., F.E.I., M.B.), Laboratory of Molecular Gerontology (M.S.-K.), National Institute on Aging, National Institutes of Health, Baltimore, Maryland
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Morten Scheibye-Knudsen
Laboratory of Clinical Investigation (S.M.K.-W., I.G.-M., F.E.I., M.B.), Laboratory of Molecular Gerontology (M.S.-K.), National Institute on Aging, National Institutes of Health, Baltimore, Maryland
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Fred E. Indig
Laboratory of Clinical Investigation (S.M.K.-W., I.G.-M., F.E.I., M.B.), Laboratory of Molecular Gerontology (M.S.-K.), National Institute on Aging, National Institutes of Health, Baltimore, Maryland
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Michel Bernier
Laboratory of Clinical Investigation (S.M.K.-W., I.G.-M., F.E.I., M.B.), Laboratory of Molecular Gerontology (M.S.-K.), National Institute on Aging, National Institutes of Health, Baltimore, Maryland
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Abstract

The orphan nuclear receptor estrogen-related receptor alpha (ERRα) directs the transcription of nuclear genes involved in energy homeostasis control and the regulation of mitochondrial mass and function. A crucial role for controlling ERRα-mediated target gene expression has been ascribed to the biarylpyrazole compound 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251) through direct binding to and destabilization of ERRα protein. Here, we provide evidence that structurally related AM251 analogs also have negative impacts on ERRα protein levels in a cell-type-dependent manner while having no deleterious actions on ERRγ. We show that these off-target cellular effects of AM251 are mediated by proteasomal degradation of nuclear ERRα. Cell treatment with the nuclear export inhibitor leptomycin B did not prevent AM251-induced destabilization of ERRα protein, whereas proteasome inhibition with MG132 stabilized and maintained its DNA-binding function, indicative of ERRα being a target of nuclear proteasomal complexes. NativePAGE analysis revealed that ERRα formed a ∼220-kDa multiprotein nuclear complex that was devoid of ERRγ and the coregulator peroxisome proliferator-activated receptor γ coactivator-1. AM251 induced SUMO-2,3 incorporation in ERRα in conjunction with increased protein kinase C activity, whose activation by phorbol ester also promoted ERRα protein loss. Down-regulation of ERRα by AM251 or small interfering RNA led to increased mitochondria biogenesis while negatively impacting mitochondrial membrane potential. These results reveal a novel molecular mechanism by which AM251 and related compounds alter mitochondrial physiology through destabilization of ERRα.

Footnotes

  • This research was supported entirely by the Intramural Research Program of the National Institutes of Health [National Institute on Aging].

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • dx.doi.org/10.1124/mol.112.082651.

  • Received September 26, 2012.
  • Accepted October 12, 2012.
  • U.S. government work not protected by U.S. copyright.
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Molecular Pharmacology: 83 (1)
Molecular Pharmacology
Vol. 83, Issue 1
1 Jan 2013
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Research ArticleArticle

Proteasomal Degradation of ERRα by AM251

Susan M. Krzysik-Walker, Isabel González-Mariscal, Morten Scheibye-Knudsen, Fred E. Indig and Michel Bernier
Molecular Pharmacology January 1, 2013, 83 (1) 157-166; DOI: https://doi.org/10.1124/mol.112.082651

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Research ArticleArticle

Proteasomal Degradation of ERRα by AM251

Susan M. Krzysik-Walker, Isabel González-Mariscal, Morten Scheibye-Knudsen, Fred E. Indig and Michel Bernier
Molecular Pharmacology January 1, 2013, 83 (1) 157-166; DOI: https://doi.org/10.1124/mol.112.082651
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