PGRMC2 is an Intracellular Heme 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 highly reactive metabolite is delivered from mitochondria to hemoproteins throughout the cell remains poorly defined ^{3, 4} . Here, we show that PGRMC2 is required for delivery of labile, or signaling heme, to the nucleus. Deletion of PGMRC2 in brown fat, which has a high demand for heme, reduced labile heme in the nucleus and increased stability of the heme-responsive transcriptional repressors Rev-Erbα and BACH1. Ensuing alterations in gene expression spawn 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. In 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 heme transport, reveal the impact of adipose tissue heme dynamics on physiology, and suggest that modulation of PGRMC2 may revert obesity-linked defects in adipocytes.