Diurnal cycle influences peripheral and brain iron levels in mice

Abstract

Iron movement between organ pools involves a dynamic equilibrium of iron efflux and uptake, and homeostatic mechanisms are likely involved in providing iron to cells and organs when required. Daily iron levels in the plasma pool fluctuate with the diurnal cycle, but clear explanations regarding the objectives and regulation of the flux are lacking. The association between diurnal cycle and iron flux is relevant in the disease of restless legs syndrome (RLS), where individuals display diurnal deficits in motor control, have impaired brain iron metabolism, and perhaps altered iron uptake from the plasma pool. The goal of the present study was to examine diurnal variations in peripheral and regional brain iron to evaluate iron flux between organs in iron-sufficient and iron-deficient mice. In mice fed control diet, liver iron was elevated 30-40%, and plasma iron was reduced 20-30% in the active dark period compared with the inactive light phase. Dietary iron deficiency eliminated this variation in liver iron in male and female mice and in plasma iron in male mice. Reductions in ventral midbrain and nucleus accumbens iron and ferritin were apparent in iron-deficient mice during both diurnal phases, but only during the light phase was an approximately 25% reduction in whole brain iron observed, suggesting different brain iron requirements between phases. These data demonstrate that iron flux between organs is sensitive to diurnal regulatory biology. Importantly, variations in brain iron may have temporal implications regarding neural functioning and may contribute to the diurnal cycle-dependent symptoms of RLS.

Ribosome profiling reveals the rhythmic liver translatome and circadian clock regulation by upstream open reading frames

“…We did not observe high-amplitude rhythms in the expression of IRPs or their known regulators (Supplemental Fig. S11; please note low amplitude rhythms for Ireb2), and it is conceivable that rhythmicity occurs at the level of available, bioactive iron in the hepatocyte (day/night changes in hepatic total iron have been reported) (Unger et al 2009), of O 2 pressure/consumption (Peek et al 2013), or of reactive oxygen species (Khapre et al 2011). Together with the oscillations in mRNA abundance seen for multiple other iron metabolic genes, the rhythmic regulation of IRE-containing transcripts uncovers a previously unappreciated extent of temporal control in this physiologically important pathway.…”

Age-dependent and gender-specific changes in mouse tissue iron by strain

“…There is evidence that diurnal cycle influences iron homeostasis (Unger et al, 2009). While all mice were sacrificed during daytime hours, between 9am to 5pm, we did not standardize time of sacrifice.…”

A Novel Model for Brain Iron Uptake: Introducing the Concept of Regulation

“…It fails to provide a mechanism for regulating brain iron uptake or to account for the substantial iron requirements of the ECs. This model also fails to account for several important aspects of cerebral iron transport: (1) the observed rate of iron transport is significantly greater than transferrin import, implying a segregation of iron and Tf within the ECs, (2) there is no mechanism to induce release of the tightly bound Tf at the abluminal membrane, (3) there is no mechanism to return the receptor to the luminal membrane, 5 (4) there is no mechanism for recharging apotransferrin after the delivery of iron to neural cells, 6 and (5) there is no mechanism for regulating the expression of Tf receptors in response to intracellular iron.…”