Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbalpha.
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.
Wu
Nan
N
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Yin
Lei
L
Hanniman
Elyisha A
EA
Joshi
Shree
S
Lazar
Mitchell A
MA
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D019069:Cell Respiration / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology*; D015870:Gene Expression; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria; D041681:NIH 3T3 Cells; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D010101:Oxygen Consumption / Q000502:physiology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D020218:Response Elements; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; C064353:NR1D1 protein, human; C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D015534:Trans-Activators; D014157:Transcription Factors; D006418:Heme; D000624:5-Aminolevulinate Synthetase