Role of iron and aluminum in brain metabolism

Ferritin is a storage protein for excess iron. It is composed of heavy (H) and light (L) chain subunits. In brain and other tissues, the ferritin heavy chain (FTH) is coded by two mRNAs of 1.1kb and 1.4kb. The 1.4kb mRNA has an additional 279nt in the 3'UTR (untranslated region) upstream to the polyA+ tail. In all other respects, the two mRNAs are identical. The 1.4kb FTH mRNA is most abundant in the brain compared to other tissues such as liver, heart, pancreas, intestine, skeletal muscle, kidney and placenta. Earlier studies have found that of the two FTH mRNAs, the 1.1kb is more abundant than the 1.4kb mRNA in the human liver. It is shown in this study that even in the human brain, the 1.1 kb mRNA is more abundant than the 1.4kb mRNA. Human fetal brain shows the presence of a non-ferritin mRNA (1.55kb) containing a part of, or the entire 279nt which is present in the 3'UTR of the 1.4kb FTH mRNA. No similar mRNA is detected in the human adult brain. Changes in the genome during the life span of humans as with any organism are unlikely. The above observation, therefore, suggests the occurrence of development-dependent changes in human brain cells that result in the transcriptional switching-off of a certain yet unidentified gene between fetal and adult stages of life. Aluminum (Al³⁺) is a metal ion that has no physiological function. But as it resembles iron (Fe) in its co-ordination chemistry, it is suggested that Al³⁺ uses the transport mechanism of iron in-vivo. Earlier researchers have isolated Al³⁺-transferrin and Al³⁺-ferritin complexes from human serum and the brains of aluminum fed rats. Al³⁺ has been shown to inhibit several regulatory enzymes of cellular metabolism. We show in this study the effect of the metal ion on two regulatory enzymes, namely aconitase and isocitrate dehydrogenase (ICDH). Cytosolic aconitase is a regulating protein of ferritin biosynthesis and is not affected by Al³⁺ while ICDH, a key regulatory enzyme and control point of the TCA cycle, is inhibited by the metal ion in a concentration-dependent manner. Al³⁺ exhibits a competitive inhibition with respect to NADP⁺ (a substrate for ICDH) with a K_i of 7.41 X 10^-4M. A similar inhibition in-vivo of ICDH, may deregulate the TCA cycle, affecting not only the complete oxidation of glucose, but also the synthesis of amino acids and porphyrins.