Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbalpha.
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Wu N, Yin L, Hanniman EA, Joshi S, Lazar MA
Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbalpha.
Genes Dev. 2009 Sep 15;23(18):2201-9. doi: 10.1101/gad.1825809. Epub 2009 Aug 26.
- PubMed ID
- 19710360 [ View in PubMed]
- 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.