Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and Mental Health, Kenneth Myer Building, The University of Melbourne, Parkville, Victoria 3052, Australia.
Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
Biochim Biophys Acta Mol Basis Dis. 2018 Sep;1864(9 Pt B):2793-2813. doi: 10.1016/j.bbadis.2018.05.007. Epub 2018 May 16.
Many biological processes result from the coupling of metabolic pathways. Considering this, proliferation depends on adequate iron and polyamines, and although iron-depletion impairs proliferation, the metabolic link between iron and polyamine metabolism has never been thoroughly investigated. This is important to decipher, as many disease states demonstrate co-dysregulation of iron and polyamine metabolism. Herein, for the first time, we demonstrate that cellular iron levels robustly regulate 13 polyamine pathway proteins. Seven of these were regulated in a conserved manner by iron-depletion across different cell-types, with four proteins being down-regulated (i.e., acireductone dioxygenase 1 [ADI1], methionine adenosyltransferase 2α [MAT2α], Antizyme and polyamine oxidase [PAOX]) and three proteins being up-regulated (i.e., S-adenosyl methionine decarboxylase [AMD1], Antizyme inhibitor 1 [AZIN1] and spermidine/spermine-N-acetyltransferase 1 [SAT1]). Depletion of iron also markedly decreased polyamine pools (i.e., spermidine and/or spermine, but not putrescine). Accordingly, iron-depletion also decreased S-adenosylmethionine that is essential for spermidine/spermine biosynthesis. Iron-depletion additionally reduced H-spermidine uptake in direct agreement with the lowered levels of the polyamine importer, SLC22A16. Regarding mechanism, the "reprogramming" of polyamine metabolism by iron-depletion is consistent with the down-regulation of ADI1 and MAT2α, and the up-regulation of SAT1. Moreover, changes in ADI1 (biosynthetic) and SAT1 (catabolic) partially depended on the iron-regulated changes in c-Myc and/or p53. The ability of iron chelators to inhibit proliferation was rescuable by putrescine and spermidine, and under some conditions by spermine. Collectively, iron and polyamine metabolism are intimately coupled, which has significant ramifications for understanding the integrated role of iron and polyamine metabolism in proliferation.
许多生物过程是代谢途径偶联的结果。考虑到这一点，增殖依赖于足够的铁和多胺，尽管铁耗竭会损害增殖，但铁和多胺代谢之间的代谢联系从未被彻底研究过。这一点很重要，因为许多疾病状态都表现出铁和多胺代谢的共同失调。在此，我们首次证明细胞内铁水平强烈调节 13 种多胺途径蛋白。其中 7 种在不同细胞类型中铁耗竭时以保守的方式被调节，其中 4 种蛋白下调（即还原酮二加氧酶 1[ADI1]、甲硫氨酸腺苷转移酶 2α[MAT2α]、抗霉素和多胺氧化酶[PAOX]），3 种蛋白上调（即 S-腺苷甲硫氨酸脱羧酶[AMD1]、抗霉素抑制剂 1[AZIN1]和亚精胺/精脒-N-乙酰基转移酶 1[SAT1]）。铁耗竭还显著降低了多胺池（即亚精胺和/或精胺，但不是腐胺）。因此，铁耗竭也降低了 S-腺苷甲硫氨酸，这是亚精胺/精胺生物合成所必需的。铁耗竭还降低了 H-亚精胺的摄取，这与多胺转运蛋白 SLC22A16 水平的降低直接一致。关于机制，铁耗竭对多胺代谢的“重编程”与 ADI1 和 MAT2α 的下调以及 SAT1 的上调一致。此外，ADI1（合成）和 SAT1（分解代谢）的变化部分依赖于铁调节的 c-Myc 和/或 p53 的变化。铁螯合剂抑制增殖的能力可被腐胺和亚精胺挽救，在某些条件下也可被精胺挽救。总之，铁和多胺代谢密切相关，这对理解铁和多胺代谢在增殖中的综合作用具有重要意义。
