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 Devjournal_title
Genes & developmentauthors
Wu N,Yin L,Hanniman EA,Joshi S,Lazar MAdoi
10.1101/gad.1825809subject
Has Abstractpub_date
2009-09-15 00:00:00pages
2201-9issue
18eissn
0890-9369issn
1549-5477pii
gad.1825809journal_volume
23pub_type
杂志文章abstract::In budding yeast, a switch between the mutually exclusive pathways of cell cycle progression and conjugation is controlled at Start in late G1 phase. Mating pheromones promote conjugation by arresting cells in G1 phase before Start. Pheromone-induced cell cycle arrest requires a functional FAR1 gene. We have found tha...
journal_title:Genes & development
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