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.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
5-Aminolevulinate Synthetase / metabolism
-
Animals
-
Cell Line
-
Cell Proliferation
-
Cell Respiration / physiology
-
Cells, Cultured
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / metabolism*
-
Feedback, Physiological / physiology*
-
Gene Expression
-
Gene Expression Regulation
-
Heat-Shock Proteins / metabolism
-
Heme / metabolism*
-
Homeostasis / physiology*
-
Humans
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Mitochondria
-
NIH 3T3 Cells
-
Nuclear Receptor Subfamily 1, Group D, Member 1
-
Oxygen Consumption / physiology
-
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
-
Receptors, Cytoplasmic and Nuclear / genetics
-
Receptors, Cytoplasmic and Nuclear / metabolism*
-
Receptors, Retinoic Acid / metabolism
-
Response Elements
-
Trans-Activators / metabolism
-
Transcription Factors / metabolism
Substances
-
DNA-Binding Proteins
-
Heat-Shock Proteins
-
NR1D1 protein, human
-
Nr1d1 protein, mouse
-
Nuclear Receptor Subfamily 1, Group D, Member 1
-
PPARGC1A protein, human
-
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
-
Ppargc1a protein, mouse
-
Receptors, Cytoplasmic and Nuclear
-
Receptors, Retinoic Acid
-
Trans-Activators
-
Transcription Factors
-
Heme
-
5-Aminolevulinate Synthetase