NOTICE -- Login operations are currently offline due to an unscheduled disruption. We are waiting for LDAP services to be re-instated. We apologize for the inconvenience - June 24, 2021
John York
Last active: 3/30/2020

Modulation of sulfur assimilation metabolic toxicity overcomes anemia and hemochromatosis in mice.

Hale AT, Brown RE, Luka Z, Hudson BH, Matta P, Williams CS, York JD
Adv Biol Regul. 2020 76: 100694

PMID: 32019729 · PMCID: PMC7230019 · DOI:10.1016/j.jbior.2020.100694

Sulfur assimilation is an essential metabolic pathway that regulates sulfation, amino acid metabolism, nucleotide hydrolysis, and organismal homeostasis. We recently reported that mice lacking bisphosphate 3'-nucleotidase (BPNT1), a key regulator of sulfur assimilation, develop iron-deficiency anemia (IDA) and anasarca. Here we demonstrate two approaches that successfully reduce metabolic toxicity caused by loss of BPNT1: 1) dietary methionine restriction and 2) overproduction of a key transcriptional regulator hypoxia inducible factor 2α (Hif-2a). Reduction of methionine in the diet reverses IDA in mice lacking BPNT1, through a mechanism of downregulation of sulfur assimilation metabolic toxicity. Gaining Hif-2a acts through a different mechanism by restoring iron homeostatic gene expression in BPNT1 deficient mouse intestinal organoids. Finally, as loss of BPNT1 impairs expression of known genetic modifiers of iron-overload, we demonstrate that intestinal-epithelium specific loss of BPNT1 attenuates hepatic iron accumulation in mice with homozygous C282Y mutations in homeostatic iron regulator (HFE), the most common cause of hemochromatosis in humans. Overall, our study uncovers genetic and dietary strategies to overcome anemia caused by defects in sulfur assimilation and identifies BPNT1 as a potential target for the treatment of hemochromatosis.

Copyright © 2020 Elsevier Ltd. All rights reserved.

MeSH Terms (0)

Connections (2)

This publication is referenced by other Labnodes entities: