Transcriptional and post-transcriptional regulation of ferritin: modulation by oxalomalate.

With rare exceptions, virtually all studied organisms from Archaea to man are dependent on iron for survival. Despite the ubiquitous distribution and abundance of iron in the biosphere, iron-dependent life must contend with the paradoxical hazards of iron deficiency and iron overload, each with its serious or fatal consequences. Homeostatic mechanisms regulating the absorption, transport, storage, and mobilization of cellular iron are therefore of critical importance in iron metabolism, and a rich biology and chemistry underlie all of these mechanisms. Ferritins are among the most ancient proteins of iron metabolism, found substantially conserved in species from bacteria to plants to man. Ferritin is required for intracellular iron storage; its biosynthesis is regulated both transcriptionally, through iron–dependent and iron-independent factors, and translationally by the action of iron-regulatory proteins (IRP1 and IRP2). These regulations prevent iron excess from promoting the formation of reactive oxygen species (ROS). We have recently demonstrated that oxalomalate (OMA, -hydroxy--oxalosuccinic acid), a competitive inhibitor of aconitase, an enzyme of the citric acid cycle, remarkably decreases the RNA-binding activity of IRP1. The aim of the present study has been to investigate the effect of OMA on the translation of ferritin. In an attempt to verify this hypothesis, we evaluated the levels of ferritin in various cell types cultured with OMA and we found that this compound increases the intracellular ferritin content. In addition, we analyzed whether the OMA effect on the modulation of ferritin expression may result also from a transcriptional regulation. We observed an increase in ferritin mRNA levels and an enhanced transcription of H-ferritin gene induced by OMA. We suppose that OMA could play a role in controlling ferritin expression both at post-transcriptional and at transcriptional level, leading to a major amount of protein. Finally, the OMA-induced ferritin overexpression decreases ROS formation and cellular lipid peroxidation, thus protecting cells from iron-dependent oxidative injury. In conclusion, these data show that an inhibitor of aconitase, OMA, besides being involved in energetic metabolism, is able to control ferritin expression, probably through molecular mechanisms of either post-transcriptional regulation or transcriptional modulation, with advantageous consequences for the cell.