Iron regulatory proteins (IRP) modulate the use of
mRNA-encoding
proteins that are involved in the transport, storage and use of
iron. Several new potential
mRNA targets for IRP were recently identified:
divalent metal transporter-1 (DMT-1) and
ferroportin, which are critical regulators of
iron absorption in the gut and of
iron cycling between various tissues of the body. Although this may extend the reach of IRP to other processes that are important for maintaining body
iron homeostasis, the extent to which IRP modulate other physiological processes that are altered in response to changes in
iron availability is not clear. However, in the past several years, targets for IRP and IRP-like
proteins were identified in eukaryotes and prokaryotes in the
tricarboxylic acid (TCA) cycle and electron-transport chain. In mammals, this includes the
mRNA that encodes the TCA-cycle
enzyme mitochondrial
aconitase (m-acon). Recent work established that m-acon expression is translationally regulated by
iron in a manner that is strongly correlated with IRP
RNA-binding activity. Interestingly, these studies also demonstrate that IRP regulate their
mRNA targets in a hierarchical manner. The changes in m-acon synthesis and abundance in liver during
iron deficiency fail to affect TCA-cycle capacity but are associated with a significant upregulation of mitochondrial export of radiolabeled
citrate. We conclude that IRP are required for the regulation of physiological pathways that include but are not limited to
iron metabolism, and as such, IRP are critical factors in the adaptive response to
iron deficiency.