The Ferritin Genes: Structure, Expression, zyx and Regulation zy HAMISH N. MUNRO," NAZNEEN AZIZ,b ELIZABETH A. LEIBOLD,b MARY MURRAY zyx ,b JACK ROGERS,b J. KEITH VASS,b AND KRISTIN WHITE" zy "USDA Human Nutrition Research Center on Aging at Tufts University Boston, Massachusetts 02111 bDepartment zyxwv of Applied Biological Sciences Massachusetts Institute of Technology Cambridge, Massachusetts 02138 INTRODUCIlON Storage of iron in the tissues occurs in the form of ferritin and hemosiderin. Evidence regarding the latter' supports the thesis that hemosiderin originates from ferritin that has undergone intracellular digestion of its protein shell, leaving the iron core, usually located inside the inspissated remains of secondary lysoso- ma1 vesicles. Ferritin and hemosiderin are thus components of a continuum. This paper focuses on fenitin. Ferritin has been identified in all types of living organisms: animals, plants, molds, and bacteria.2 Within the protein shell of ferritin, iron is first oxidized to the ferric state for storage as ferric oxyhydroxide. The advantage of this mecha- nism is that it removes excess iron from the cell sap where it could otherwise participate in peroxidation mechanisms. For example, a single parenteral dose of iron salts administered to rats has been found to result in a burst of ethane exhaled by animal^.^ This is due to peroxidation of membrane-associated omega-3-fatty acids, a response that can be suppressed by raising intake of vitamin E. Such experiments and others emphasize that iron can generate free radicals detrimental to cell membranes and to other molecular structures. Ferritin is the antidote for this phenomenon. The hollo'w protein shell of ferritin is penetrated by channels through which iron enters and exits from the ferritin cavity. The protein shell has a molecular weight of about 5 x105, and is made up of 24 subunits of two types, a slightly heavier H (mol. wt. about 21,000) and a lighter subunit L (mol. wt. about 20,000). When ferritin isolated from a tissue is subjected to isoelectric focusing, it segre- gates into a series of isoferritins with varying proportions of H and L subunits in the shell.4TABLE 1 shows that the H zyxwv : L ratios for isoferritins in rat tissues display a progression throughout the isofocusing gradient, suggesting that the surface charges of H and L subunits differ and their proportions thus determine the PI of the ferritin shell. It will be noted that the H : L ratios for a given isofocusing pl are quite different in rat heart and liver (TABLE 11, suggesting that the H and/or L subunits in these two tissues have different surface charges. This could be due to tissue-specific differences in primary amino acid sequences or to posttranslational modifications from glycosylation or other changes. A knowledge of the number of expressed ferritin genes could allow a decision as to which explanation is favored. z 113