PGRMC2 is an intracellular haem chaperone critical for adipocyte function

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, Bruno Conti, Laura A. Solt, Douglas Kojetin, Christopher G. Parker, John J. Peluso, James K. Pru, Gary Siuzdak, Benjamin F. Cravatt and Enrique Saez ()
Additional contact information
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
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
John J. Peluso: University of Connecticut Health Center
James K. Pru: Washington State University
Gary Siuzdak: The Scripps Research Institute
Benjamin F. Cravatt: The Scripps Research Institute
Enrique Saez: The Scripps Research Institute

Nature, 2019, vol. 576, issue 7785, 138-142

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41586-019-1774-2 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:576:y:2019:i:7785:d:10.1038_s41586-019-1774-2

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-019-1774-2

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().