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

Israa Sharkia, Tal Hadad Erlich, Nadine Landolina, Miri Assayag, Alex Motzik, Inbal Rachmin, Gillian Kay, Ziv Porat, Sagi Tshori, Neville Berkman, Francesca Levi-Schaffer, Ehud Razin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)204-214.e8
JournalJournal of Allergy and Clinical Immunology
Volume140
Issue number1
DOIs
StatePublished - Jul 2017

Bibliographical note

Publisher Copyright:
© 2016 American Academy of Allergy, Asthma & Immunology

Keywords

  • Allergy
  • asthma
  • cytokines
  • degranulation
  • mast cells
  • microphthalmia transcription factor
  • mitochondria
  • pyruvate dehydrogenase

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