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Research ArticleArticle

Salicylic Acid Induces Mitochondrial Injury by Inhibiting Ferrochelatase Heme Biosynthesis Activity

Vipul Gupta, Shujie Liu, Hideki Ando, Ryohei Ishii, Shumpei Tateno, Yuki Kaneko, Masato Yugami, Satoshi Sakamoto, Yuki Yamaguchi, Osamu Nureki and Hiroshi Handa
Molecular Pharmacology December 2013, 84 (6) 824-833; DOI: https://doi.org/10.1124/mol.113.087940
Vipul Gupta
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (V.G., S.L., H.A., S.T., Y.K., M.Y., S.S., Y.Y., H.H.); and Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo, Japan (R.I., O.N.)
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Shujie Liu
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (V.G., S.L., H.A., S.T., Y.K., M.Y., S.S., Y.Y., H.H.); and Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo, Japan (R.I., O.N.)
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Hideki Ando
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (V.G., S.L., H.A., S.T., Y.K., M.Y., S.S., Y.Y., H.H.); and Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo, Japan (R.I., O.N.)
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Ryohei Ishii
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (V.G., S.L., H.A., S.T., Y.K., M.Y., S.S., Y.Y., H.H.); and Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo, Japan (R.I., O.N.)
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Shumpei Tateno
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (V.G., S.L., H.A., S.T., Y.K., M.Y., S.S., Y.Y., H.H.); and Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo, Japan (R.I., O.N.)
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Yuki Kaneko
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (V.G., S.L., H.A., S.T., Y.K., M.Y., S.S., Y.Y., H.H.); and Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo, Japan (R.I., O.N.)
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Masato Yugami
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (V.G., S.L., H.A., S.T., Y.K., M.Y., S.S., Y.Y., H.H.); and Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo, Japan (R.I., O.N.)
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Satoshi Sakamoto
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (V.G., S.L., H.A., S.T., Y.K., M.Y., S.S., Y.Y., H.H.); and Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo, Japan (R.I., O.N.)
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Yuki Yamaguchi
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (V.G., S.L., H.A., S.T., Y.K., M.Y., S.S., Y.Y., H.H.); and Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo, Japan (R.I., O.N.)
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Osamu Nureki
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (V.G., S.L., H.A., S.T., Y.K., M.Y., S.S., Y.Y., H.H.); and Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo, Japan (R.I., O.N.)
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Hiroshi Handa
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (V.G., S.L., H.A., S.T., Y.K., M.Y., S.S., Y.Y., H.H.); and Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo, Japan (R.I., O.N.)
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Abstract

Salicylic acid is a classic nonsteroidal anti-inflammatory drug. Although salicylic acid also induces mitochondrial injury, the mechanism of its antimitochondrial activity is not well understood. In this study, by using a one-step affinity purification scheme with salicylic acid–immobilized beads, ferrochelatase (FECH), a homodimeric enzyme involved in heme biosynthesis in mitochondria, was identified as a new molecular target of salicylic acid. Moreover, the cocrystal structure of the FECH–salicylic acid complex was determined. Structural and biochemical studies showed that salicylic acid binds to the dimer interface of FECH in two possible orientations and inhibits its enzymatic activity. Mutational analysis confirmed that Trp301 and Leu311, hydrophobic amino acid residues located at the dimer interface, are directly involved in salicylic acid binding. On a gel filtration column, salicylic acid caused a shift in the elution profile of FECH, indicating that its conformational change is induced by salicylic acid binding. In cultured human cells, salicylic acid treatment or FECH knockdown inhibited heme synthesis, whereas salicylic acid did not exert its inhibitory effect in FECH knockdown cells. Concordantly, salicylic acid treatment or FECH knockdown inhibited heme synthesis in zebrafish embryos. Strikingly, the salicylic acid–induced effect in zebrafish was partially rescued by FECH overexpression. Taken together, these findings illustrate that FECH is responsible for salicylic acid–induced inhibition of heme synthesis, which may contribute to its antimitochondrial and anti-inflammatory function. This study establishes a novel aspect of the complex pharmacological effects of salicylic acid.

Footnotes

    • Received June 16, 2013.
    • Accepted September 16, 2013.
  • This work was supported in part by the Japanese Ministry of Education, Culture, Sports, Science, and Technology [Grants-in-Aid for Scientific Research on Innovative Areas in “Chemical Biology of Natural Products” and “Transcription Cycle”]; the Japan Society for the Promotion of Science [Grant-in-Aid for Scientific Research (A)]; the Japanese Ministry of Health, Labor, and Welfare [Health Labor Sciences Research Grants for Research on New Drug Development]; and the New Energy and Industrial Technology Development Organization (NEDO) of Japan [Research and Development Projects in Cooperation with Academic Institutions from NEDO].

  • dx.doi.org/10.1124/mol.113.087940.

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

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 84 (6)
Molecular Pharmacology
Vol. 84, Issue 6
1 Dec 2013
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Research ArticleArticle

Ferrochelatase Is a Novel Target of Salicylic Acid

Vipul Gupta, Shujie Liu, Hideki Ando, Ryohei Ishii, Shumpei Tateno, Yuki Kaneko, Masato Yugami, Satoshi Sakamoto, Yuki Yamaguchi, Osamu Nureki and Hiroshi Handa
Molecular Pharmacology December 1, 2013, 84 (6) 824-833; DOI: https://doi.org/10.1124/mol.113.087940

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Research ArticleArticle

Ferrochelatase Is a Novel Target of Salicylic Acid

Vipul Gupta, Shujie Liu, Hideki Ando, Ryohei Ishii, Shumpei Tateno, Yuki Kaneko, Masato Yugami, Satoshi Sakamoto, Yuki Yamaguchi, Osamu Nureki and Hiroshi Handa
Molecular Pharmacology December 1, 2013, 84 (6) 824-833; DOI: https://doi.org/10.1124/mol.113.087940
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