IRON DIFFERENTIALLY STIMULATES TRANSLATION OF MITOCHONDRIAL ACONITASEAND FERRITIN MESSENGER-RNAS IN MAMMALIAN-CELLS - IMPLICATIONS FOR IRON REGULATORY PROTEINS AS REGULATORS OF MITOCHONDRIAL CITRATE UTILIZATION

Utilization of mRNAs containing iron-responsive elements (IREs) is mod ulated by iron-regulated RNA-binding proteins (iron regulatory protein s). We examine herein whether iron differentially affects translation of ferritin and mitochondrial aconitase (m-Acon) mRNAs because they co ntain a similar but not identical IRE in their 5'-untranslated regions . First, we demonstrate that m-Acon synthesis is iron-regulated in mam malian cells. In HL-60 cells, hemin (an iron source) stimulated m-Acon synthesis 3-fold after 4 h compared with cells treated with an iron c helator (Desferal). Furthermore, hemin stimulated m-Acon synthesis 2-4 -fold in several cell lines. Second, me show that iron modulates the p olysomal association of m-Acon mRNA. We observed m-Acon mRNA in both r ibonucleoprotein and polyribosomal fractions of HL-60 cells. Hemin sig nificantly increased the polyribosomal association and decreased the r ibonucleoprotein abundance of m-Acon mRNA in HL-60 cells. Third, our r esults indicate that iron differentially regulates translation of m-Ac on and ferritin mRNAs. A dose response to hemin in HL-60 cells elicite d a 2-2.4-fold increase in m-Acon synthesis within 5 h compared with u ntreated cells, whereas ferritin synthesis was stimulated 20-100-fold. We conclude that iron modulates m-Acon synthesis at the translational level and that iron regulatory proteins appear to differentially affe ct translation of IRE-containing mRNAs.