Chloramphenicol-induced mitochondrial dysfunction is associated with decreased transferrin receptor expression and ferritin synthesis in K562 cells and is unrelated to IRE-IRP interactions

Chloramphenicol is an antibiotic that consistently suppresses the bone marr ow and induces sideroblastic anemia. It is also a rare cause of aplastic an emia. These toxicities are thought to be related to mitochondrial dysfuncti on, since chloramphenicol inhibits mitochondrial protein synthesis. We hypo thesized that chloramphenicol-induced mitochondrial impairment alters the s ynthesis of ferritin and the transferrin receptor. After treating K562 eryt hroleukemia cells with a therapeutic dose of chloramphenicol (10 mu g/ml) f or 4 days, there was a marked decrease in cell surface transferrin receptor expression and de novo ferritin synthesis associated with significant decr eases in cytochrome c oxidase activity, ATP levels, respiratory activity, a nd cell growth. Decreases in the transferrin receptor and ferritin were ass ociated with reduced and unchanged message levels, respectively. The mechan ism by which mitochondrial dysfunction alters these important proteins in i ron homeostasis is not clear. A global decrease in synthetic processes seem s unlikely, since the expression of the cellular adhesion proteins VLA4 and CD58 was not significantly decreased by chloramphenicol, nor were the mess age levels of p-actin or ferritin. The alterations were not accompanied by changes in binding of the iron response protein (IRP) to the iron-responsiv e element (IRE), although cytosolic aconitase activity was reduced by 27% i n chloramphenicol-treated cells. A disturbance in iron homeostasis due to a lterations in the transferrin receptor and ferritin may explain the hypochr omic-microcytic anemia and the accumulation of nonferritin iron in the mito chondria in some individuals after chloramphenicol therapy. Also, these stu dies provide evidence of a link between mitochondrial impairment and iron m etabolism in K562 cells. (C) 1999 Wiley-Liss, Inc.