Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 53, Issue 2, Pages 366-374Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2012.03.007
Keywords
Heme oxygenase-1; Iron homeostasis; Free radicals
Funding
- National Health and Medical Research Council (NHMRC) of Australia
- Biomedical Research Council [BMRC 06/1/21/19/475]
- NHMRC
- University of Sydney
- University of Sydney Medical Foundation
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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. (C) 2012 Elsevier Inc. All rights reserved.
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