title: Sustained expression of heme oxygenase-1 alters iron homeostasis in nonerythroid cells.
abstract: Heme oxygenases initiate the catabolism of heme, releasing carbon monoxide, iron, and biliverdin. Sustained induction of heme oxygenase-1 (HO-1) in nonerythroid cells plays a key role in many pathological processes, yet the effect of long-term HO-1 expression on cellular iron metabolism in the absence of exogenous heme is poorly understood. Here we report that in a model nonerythroid cell, both transient and stable HO-1 expression increased heme oxygenase activity, but total cellular heme content was decreased only with transient enzyme expression. Sustained HO-1 activity increased the expression of both the mitochondrial iron importer mitoferrin-2 and the rate-limiting enzyme in heme synthesis, aminolevulinate synthase-1, and it augmented the mitochondrial content of heme. Also, the expression of transferrin receptor-1 and the activities of iron-regulatory proteins 1 and 2 decreased, whereas total labile iron and the regulatory activity of the heme-binding transcription factor Bach1 were unaltered. In addition, stable, but not transient, HO-1 expression decreased the activities of aconitase, as well as increasing proteasomal degradation of ferritin. Together, our results reveal a novel and coordinated adaptive response of nonerythroid cells to sustained HO-1 induction that has an impact on cellular iron homeostasis.
authors.affiliation: Centre for Vascular Research, School of Medical Sciences (Pathology) and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.forename: Maria E
authors.initials: ME
authors.lastname: Lönn
authors.forename: Xiangcong
authors.initials: X
authors.lastname: Xu
authors.forename: Ghassan J
authors.initials: GJ
authors.lastname: Maghzal
authors.forename: David M
authors.initials: DM
authors.lastname: Frazer
authors.forename: Shane R
authors.initials: SR
authors.lastname: Thomas
authors.forename: Barry
authors.initials: B
authors.lastname: Halliwell
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Anderson
authors.forename: Roland
authors.initials: R
authors.lastname: Stocker
mesh_terms: D000624:5-Aminolevulinate Synthetase / Q000235:genetics / Q000378:metabolism; D000154:Aconitate Hydratase / Q000235:genetics / Q000378:metabolism; D000222:Adaptation, Physiological / Q000235:genetics; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism; D005293:Ferritins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006418:Heme / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000235:genetics / Q000378:metabolism; D035942:Iron Regulatory Protein 2 / Q000235:genetics / Q000378:metabolism; D010957:Plasmids; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: D015703:Antigens, CD; C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; C068126:CD71 antigen; D027682:Cation Transport Proteins; D051856:Fanconi Anemia Complementation Group Proteins; D011990:Receptors, Transferrin; C425684:SLC25A28 protein, human; D006418:Heme; D005293:Ferritins; D007501:Iron; D051547:Heme Oxygenase-1; D000624:5-Aminolevulinate Synthetase; C546175:ACO1 protein, human; D000154:Aconitate Hydratase; C546174:IREB2 protein, human; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2