Coupling of the polyamine and iron metabolism pathways in the regulation of proliferation: Mechanistic links to alterations in key polyamine biosynthetic and catabolic enzymes

Abstract

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.

Iron Regulation in Clostridioides difficile

“…Already in the nineties an increase in polyamines in bacterial cell grown under iron-limited conditions was studied (Bergeron and Weimar, 1991). A similar close relationship between intracellular iron and polyamine content was described for cancer cells (Bae et al, 2018; Lane et al, 2018). Interestingly, siderophores like petrobactin (Lee et al, 2007), alcaligin (Challis, 2005) are formed from polyamines.…”

Modeling Snyder-Robinson Syndrome in multipotent stromal cells reveals impaired mitochondrial function as a potential cause for deficient osteogenesis

“…In this context, the increase of ferritin mRNAs (both heavy chain and light chain) is likely in response to an imbalance of iron. In fact, it was recently proposed that iron and polyamines’ metabolism are intimately linked 17 . However, reducing mitochondrial function by exposing the cells to hypoxia led to a further reduction in cell proliferation, suggesting that mitochondrial function alone is not the only variable responsible for inhibited cell growth.…”

Exogenous spermine attenuates diabetic kidney injury in rats by inhibiting AMPK/mTOR signaling pathway

“…Polyamines have a variety of biological functions, including regulating cell proliferation, differentiation and apoptosis (7,8). Polyamine metabolism, the abnormalities of which affect the progression of cardiovascular and kidney diseases, is mainly regulated by ornithine decarboxylase (ODC) and spermidine/spermine Exogenous spermine attenuates diabetic kidney injury in rats by inhibiting AMPK/mTOR signaling pathway N1-acetyltransferase (SSAT) (9). Among them, spermine has the strongest biological activity, which can play a protective role in the progression of diabetic cardiomyopathy, myocardial hypertrophy and renal ischemia/reperfusion (I/R) injury by promoting autophagy, inhibiting inflammatory reactions, oxidative stress and endoplasmic reticulum stress, and regulating calcium homeostasis (10)(11)(12).…”