Pyruvate dehydrogenase has a major role in mast cell function, and its activity is regulated by mitochondrial microphthalmia transcription factor

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:140

Article

Sharkia, Israa¹  Erlich, Tal Hadad¹  Landolina, Nadine²  Assayag, Miri³  Motzik, Alex¹  Rachmin, Inbal^1,6,7,8,9  Kay, Gillian¹  Porat, Ziv⁴  Tshori, Sagi⁵  Berkman, Neville³  Levi-Schaffer, Francesca²  Razin, Ehud¹ 

[1] Inst Med Res Israel Canada, Dept Biochem & Mol Biol, Jerusalem, Israel

[2] Hebrew Univ Jerusalem, Pharmacol & Expt Therapeut Unit, Sch Pharm, Inst Drug Res,Fac Med, Jerusalem, Israel

[3] Hadassah Hebrew Univ, Inst Pulm Med, Med Ctr, Jerusalem, Israel

[4] Hadassah Hebrew Univ, Dept Nucl Med, Med Ctr, Jerusalem, Israel

[5] Weizmann Inst Sci, Biol Serv Dept, Flow Cytometry Unit, Rehovot, Israel

[6] Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA

[7] Brigham & Womens Hosp, Dept Med, Brigham Regenerat Med Ctr, 75 Francis St, Boston, MA 02115 USA

[8] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA

[9] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

关键词: Allergy;    mast cells;    degranulation;    cytokines;    pyruvate dehydrogenase;    microphthalmia transcription factor;    asthma;    mitochondria;   

DOI  :  10.1016/j.jaci.2016.09.047

来源: Elsevier

【 摘 要 】

Background: We have recently observed that oxidative phosphorylation-mediated ATP production is essential for mast cell function. Pyruvate dehydrogenase (PDH) is the main regulator of the Krebs cycle and is located upstream of the electron transport chain. However, the role of PDH in mast cell function has not been described. Microphthalmia transcription factor (MITF) regulates the development, number, and function of mast cells. Localization of MITF to the mitochondria and its interaction with mitochondrial proteins has not been explored. Objective: We sought to explore the role played by PDH in mast cell exocytosis and to determine whether MITF is localized in the mitochondria and involved in regulation of PDH activity. Methods: Experiments were performed in vitro by using human and mouse mast cells, as well as rat basophil leukemia cells, and in vivo in mice. The effect of PDH inhibition on mast cell function was examined. PDH interaction with MITF was measured before and after immunologic activation. Furthermore, mitochondrial localization of MITF and its effect on PDH activity were determined. Results: PDH is essential for immunologically mediated degranulation of mast cells. After activation, PDH is serine dephosphorylated. In addition, for the first time, we show that MITF is partially located in the mitochondria and interacts with PDH. This interaction is dependent on the phosphorylation state of PDH. Furthermore, mitochondrial MITF regulates PDH activity. Conclusion: The association of mitochondrial MITF with PDH emerges as an important regulator of mast cell function. Our findings indicate that PDH could arise as a new target for the manipulation of allergic diseases.

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