Ferroportin deficiency impairs manganese metabolism in flatiron mice (995.1)

Abstract

Mn homeostasis must guard against neurotoxic effects of excess metal while providing a sufficient source for growth and development. Mn is absorbed from the diet by the intestine, while excess metal is excreted into bile by the liver. In vitro evidence suggests that ferroportin (Fpn), a known Fe exporter, can also export Mn. Here we examine the physiological role for Fpn in Mn metabolism using flatiron mice, a genetic model of Fpn deficiency. Flatiron mice harbor a missense mutation (H32R) affecting Fpn localization and iron export activity. These mice fully recapitulate the human iron loading disorder “ferroportin disease”. Compared to littermate wild‐type controls, Mn levels in flatiron mice are reduced in liver by 10% and in blood by 13% (P < 0.05). Using MnSOD activity as a biomarker, Mn deficiency appears as early as 6 weeks of age in flatiron mice. Pharmacokinetic studies show that intestinal 54Mn absorption is reduced in flatiron mice by 60% (P < 0.05). The sum of evidence indicates that Mn deficiency develops in flatiron mice due to reduced intestinal absorption implicating a role for Fpn in this process. Notably, flatiron mice also have 51% less Mn in bile compared to controls (P < 0.05). These data suggest that Fpn plays a key role in Mn homeostasis.Grant Funding Source: Research supported by NIH R01ES014638.