Abstract 12691: The Biological Clock Regulates Cellular Iron Homeostasis
Introduction: Iron is an essential metal for various cellular processes including mitochondrial respiration, DNA synthesis and protein synthesis. Low iron stores can disrupt any of these processes, while excess free iron increases oxidative stress. It is thus crucial to regulate iron levels to meet cellular needs while preventing excess iron accumulation. Previously it was reported that human serum iron levels show diurnal variations. However, the underlying mechanism by which iron homeostasis shows rhythmic variations and whether circadian iron regulation also exists at cellular level is unknown. Since the main function of the biological clock is to synchronize cellular demands with environmental signals such as nutrition, we hypothesize that the biological clock regulates cellular iron homeostasis to protect cells from oxidative damage.
Results: Assessment of iron levels in various tissues in mice revealed that hepatic iron levels display 24-hour diurnal variations with peaks by the onset of the active period. Furthermore, disruption of the biological clock by the deletion of circadian transcriptional activator Bmal1 caused an increase in hepatic iron levels, which was associated with a decrease in serum iron. To investigate the underlying mechanism of the clock-mediated regulation of cellular iron, we next measured the mRNA levels of iron homeostasis genes in the liver of Bmall-/- and WT mice. Our results indicated that among all proteins involved in iron homeostasis, the levels of the iron exporter, ferroportin-1 (FPN1) was significantly decreased in Bmal-/- mice. Since Bmal1 deletion is associated with an increase in cellular iron, the reduced levels of FPN1 suggests that decreased iron export through FPN1 might be the mechanism for iron accumulation in Bmal-/- livers. Bmal1 deletion was also associated with decreased levels of iron importer protein transferrin-1, consistent with a cellular signature of iron overload. Finally, mRNA expression of FPN1 and TfR1 also displayed diurnal variations.
Conclusions: Our data establish a link between the biological clock and cellular iron homeostasis pathways in mammals. Our data also suggests that FPN1 and TfR1 expression might be controlled by the clock machinery.
Author Disclosures: S. Yar: None. C. Bien Peek: None. X. Jiang: None. L. Wilsbacher: None. H. Ardehali: None.
- © 2016 by American Heart Association, Inc.