PGRMC2 is an intracellular haem chaperone critical for adipocyte function

Abstract

Heme is an essential prosthetic group of numerous proteins and a central signaling molecule in many physiologic processes 1,2. The chemical reactivity of heme requires that a network of intracellular chaperone proteins exist to avert the cytotoxic effects of free heme, but the constituents of such trafficking pathways are unknown 3,4. Heme synthesis is completed in mitochondria, with ferrochelatase (FECH) adding iron to protoporphyrin IX. How this vital but Reprints and permissions information is available at http://www.nature.com/reprints.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

PGRMC1 effects on metabolism, genomic mutation and CpG methylation imply crucial roles in animal biology and disease

“…The related protein PGRMC2 has recently been reported to chaperone heme from mitochondria to the nucleus in adipocytes, where heme regulates the transcription of genes that encode mitochondrial proteins. Lack of PGRMC2 led to altered mitochondrial morphology and function [29], superficially reminiscent of the mitochondrial effects of PGRMC1 phosphorylation mutants in MIA PaCa-2 cells [10].…”

From Synthesis to Utilization: The Ins and Outs of Mitochondrial Heme

“…These results would suggest that substrate channeling and assembly of the heme metabolon complex may be a key regulatory node for heme synthesis. Most intriguingly, the putative heme chaperones progesterone receptor membrane component 1 (PGRMC1), which has been previously proposed to deliver heme to cytochrome P450 enzymes [87][88][89] and progesterone receptor membrane component 2 (PGRMC2), which delivers heme to nuclear heme dependent transcription factors in adipose tissue [90] also interacts with FECH [83]. This would suggest that certain heme acceptor proteins may interact with the heme metabolon in order to provide an outlet valve for heme distribution to other locales.…”

“…However, the molecules and mechanisms that mobilize heme from its site of synthesis are not well defined. Recent work supports the role of a number of proteins in this distribution, including glyceraldehyde phosphate dehydrogenase (GAPDH) [91,92], PGRMC1 [83] and PGRMC2 [90]. Further, it is unclear how the demand for heme in different cellular locations regulates the distribution of heme from FECH.…”

Insights into the multifactorial causation of obesity by integrated genetic and epigenetic analysis

“…The initial focus was on genes of the leptin‐melanocortin signalling pathway as these are known to be implicated in rare monogenic forms of obesity 17–21 . Various other candidate genes were also proposed based on their role in energy homeostasis 22–25 . Particularly, the rs1805192:C > G polymorphism in peroxisome proliferator‐activated receptor gamma (PPARγ) has been firmly established as a risk factor for obesity, by both single studies and large‐scale meta‐analyses 26–29 .…”