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PGRMC2 is an intracellular haem chaperone critical for adipocyte function

Author

Listed:
  • Andrea Galmozzi

    (The Scripps Research Institute)

  • Bernard P. Kok

    (The Scripps Research Institute)

  • Arthur S. Kim

    (The Scripps Research Institute)

  • J. Rafael Montenegro-Burke

    (The Scripps Research Institute)

  • Jae Y. Lee

    (The Scripps Research Institute)

  • Roberto Spreafico

    (University of California)

  • Sarah Mosure

    (The Scripps Research Institute
    The Scripps Research Institute)

  • Verena Albert

    (The Scripps Research Institute)

  • Rigo Cintron-Colon

    (The Scripps Research Institute)

  • Cristina Godio

    (The Scripps Research Institute)

  • William R. Webb

    (The Scripps Research Institute)

  • Bruno Conti

    (The Scripps Research Institute)

  • Laura A. Solt

    (The Scripps Research Institute)

  • Douglas Kojetin

    (The Scripps Research Institute)

  • Christopher G. Parker

    (The Scripps Research Institute
    The Scripps Research Institute)

  • John J. Peluso

    (University of Connecticut Health Center)

  • James K. Pru

    (Washington State University)

  • Gary Siuzdak

    (The Scripps Research Institute
    The Scripps Research Institute)

  • Benjamin F. Cravatt

    (The Scripps Research Institute)

  • Enrique Saez

    (The Scripps Research Institute)

Abstract

Haem is an essential prosthetic group of numerous proteins and a central signalling molecule in many physiologic processes1,2. The chemical reactivity of haem means that a network of intracellular chaperone proteins is required to avert the cytotoxic effects of free haem, but the constituents of such trafficking pathways are unknown3,4. Haem synthesis is completed in mitochondria, with ferrochelatase adding iron to protoporphyrin IX. How this vital but highly reactive metabolite is delivered from mitochondria to haemoproteins throughout the cell remains poorly defined3,4. Here we show that progesterone receptor membrane component 2 (PGRMC2) is required for delivery of labile, or signalling haem, to the nucleus. Deletion of PGMRC2 in brown fat, which has a high demand for haem, reduced labile haem in the nucleus and increased stability of the haem-responsive transcriptional repressors Rev-Erbα and BACH1. Ensuing alterations in gene expression caused severe mitochondrial defects that rendered adipose-specific PGRMC2-null mice unable to activate adaptive thermogenesis and prone to greater metabolic deterioration when fed a high-fat diet. By contrast, obese-diabetic mice treated with a small-molecule PGRMC2 activator showed substantial improvement of diabetic features. These studies uncover a role for PGRMC2 in intracellular haem transport, reveal the influence of adipose tissue haem dynamics on physiology and suggest that modulation of PGRMC2 may revert obesity-linked defects in adipocytes.

Suggested Citation

  • Andrea Galmozzi & Bernard P. Kok & Arthur S. Kim & J. Rafael Montenegro-Burke & Jae Y. Lee & Roberto Spreafico & Sarah Mosure & Verena Albert & Rigo Cintron-Colon & Cristina Godio & William R. Webb & , 2019. "PGRMC2 is an intracellular haem chaperone critical for adipocyte function," Nature, Nature, vol. 576(7785), pages 138-142, December.
  • Handle: RePEc:nat:nature:v:576:y:2019:i:7785:d:10.1038_s41586-019-1774-2
    DOI: 10.1038/s41586-019-1774-2
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    Cited by:

    1. Marina Maurizio & Maria Masid & Kerry Woods & Reto Caldelari & John G. Doench & Arunasalam Naguleswaran & Denis Joly & Martín González-Fernández & Jonas Zemp & Mélanie Borteele & Vassily Hatzimanikati, 2024. "Host cell CRISPR genomics and modelling reveal shared metabolic vulnerabilities in the intracellular development of Plasmodium falciparum and related hemoparasites," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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