Author:
Wu Nan,Yin Lei,Hanniman Elyisha A.,Joshi Shree,Lazar Mitchell A.
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-erbα tightly controls the level of its own ligand. Heme binding to Rev-erbα recruits the NCoR/histone deacetylase 3 (HDAC3) corepressor complex to repress the transcription of the coactivator PGC-1α, a potent inducer of heme synthesis. Depletion of Rev-erbα derepresses PGC-1α, resulting in increased heme levels. Conversely, increased Rev-erbα reduces intracellular heme, and impairs mitochondrial respiration in a heme-dependent manner. Consistent with this bioenergetic impairment, overexpression of Rev-erbα dramatically inhibits cell growth due to a cell cycle arrest. Thus, Rev-erbα modulates the synthesis of its own ligand in a negative feedback pathway that maintains heme levels and regulates cellular energy metabolism.
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
97 articles.
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