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

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-erb alpha tightly controls the level of its own ligand. Heme binding to Rev-erb alpha recruits the NCoR/histone deacetylase 3 (HDAC3) corepressor complex to repress the transcription of the coactivator PGC-1 alpha, a potent inducer of heme synthesis. Depletion of Rev-erb alpha derepresses PGC-1 alpha, resulting in increased heme levels. Conversely, increased Rev-erb alpha reduces intracellular heme, and impairs mitochondrial respiration in a heme-dependent manner. Consistent with this bioenergetic impairment, overexpression of Rev-erb alpha dramatically inhibits cell growth due to a cell cycle arrest. Thus, Rev-erb alpha modulates the synthesis of its own ligand in a negative feedback pathway that maintains heme levels and regulates cellular energy metabolism.