title: Compartmentalization and regulation of iron metabolism proteins protect male germ cells from iron overload.
abstract: The universal importance of iron, its high toxicity, and complex chemistry present a challenge to biological systems in general and to protected compartments in particular. The high mitotic rate and avid mitochondriogenesis of developing male germ cells imply high iron requirements. Yet access to germ cells is tightly regulated by the blood-testis barrier that protects the meiotic and postmeiotic germ cells. To elucidate how iron is supplied to developing male germ cells, we analyzed iron deposition and iron transport proteins in testes of mice with iron overload and with genetic ablation of the iron regulators Hfe and iron regulatory protein 2. Iron accumulated mainly around seminiferous tubules, and only small amounts localized within the seminiferous tubules. The localization and regulation of proteins involved in iron import, storage, and export such as transferrin, transferrin receptor, the divalent metal transporter-1, cytosolic ferritin, and ferroportin strongly support a model of a largely autonomous iron cycle within seminiferous tubules. We show evidence that ferritin secretion from Sertoli cells may play an important role in iron acquisition of primary spermatocytes. During spermatogenic development iron is carried along from primary spermatocytes to spermatids, and from spermatids iron is recycled to the apical compartment of Sertoli cells, which traffic it back to a new generation of spermatocytes. Losses are replenished by the peripheral circulation. Such an internal iron cycle essentially detaches the iron homeostasis within the seminiferous tubule from the periphery and protects developing germ cells from iron fluctuations. This model explains how compartmentalization can optimize cellular and systemic nutrient homeostasis.
authors.affiliation: Faculty of Biotechnology and Food Engineering, Technion, Haifa, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Leichtmann-Bardoogo
authors.forename: Lyora A
authors.initials: LA
authors.lastname: Cohen
authors.forename: Avital
authors.initials: A
authors.lastname: Weiss
authors.forename: Britta
authors.initials: B
authors.lastname: Marohn
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schubert
authors.forename: Andreas
authors.initials: A
authors.lastname: Meinhardt
authors.forename: Esther G
authors.initials: EG
authors.lastname: Meyron-Holtz
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D005293:Ferritins / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005854:Germ Cells / Q000187:drug effects / Q000378:metabolism*; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000235:genetics / Q000378:metabolism*; D035942:Iron Regulatory Protein 2 / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics / Q000502:physiology; D011990:Receptors, Transferrin / Q000378:metabolism; D012671:Seminiferous Tubules / Q000378:metabolism; D013091:Spermatogenesis / Q000502:physiology; D013737:Testis / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse; D005293:Ferritins; D007501:Iron; D053148:Caspase 3; D035942:Iron Regulatory Protein 2