Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbalpha.

Abstract:

:Intracellular heme levels must be tightly regulated to maintain proper mitochondrial respiration while minimizing toxicity, but the homeostatic mechanisms are not well understood. Here we report a novel negative feedback mechanism whereby the nuclear heme receptor Rev-erbalpha tightly controls the level of its own ligand. Heme binding to Rev-erbalpha recruits the NCoR/histone deacetylase 3 (HDAC3) corepressor complex to repress the transcription of the coactivator PGC-1alpha, a potent inducer of heme synthesis. Depletion of Rev-erbalpha derepresses PGC-1alpha, resulting in increased heme levels. Conversely, increased Rev-erbalpha reduces intracellular heme, and impairs mitochondrial respiration in a heme-dependent manner. Consistent with this bioenergetic impairment, overexpression of Rev-erbalpha dramatically inhibits cell growth due to a cell cycle arrest. Thus, Rev-erbalpha modulates the synthesis of its own ligand in a negative feedback pathway that maintains heme levels and regulates cellular energy metabolism.

journal_name

Genes Dev

journal_title

Genes & development

authors

Wu N,Yin L,Hanniman EA,Joshi S,Lazar MA

doi

10.1101/gad.1825809

subject

Has Abstract

pub_date

2009-09-15 00:00:00

pages

2201-9

issue

18

eissn

0890-9369

issn

1549-5477

pii

gad.1825809

journal_volume

23

pub_type

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