Ferroportin deficiency impairs manganese metabolism in flatiron mice

FASEB J. 2015 Jul;29(7):2726-33. doi: 10.1096/fj.14-262592. Epub 2015 Mar 17.

Abstract

We examined the physiologic role of ferroportin (Fpn) in manganese (Mn) export using flatiron (ffe/+) mice, a genetic model of Fpn deficiency. Blood (0.0123 vs. 0.0107 mg/kg; P = 0.0003), hepatic (1.06 vs. 0.96 mg/kg; P = 0.0125), and bile Mn levels (79 vs. 38 mg/kg; P = 0.0204) were reduced in ffe/+ mice compared to +/+ controls. Erythrocyte Mn-superoxide dismutase was also reduced at 6 (0.154 vs. 0.096, P = 0.0101), 9 (0.131 vs. 0.089, P = 0.0162), and 16 weeks of age (0.170 vs. 0.090 units/mg protein/min; P < 0.0001). (54)Mn uptake after intragastric gavage was markedly reduced in ffe/+ mice (0.0187 vs. 0.0066% dose; P = 0.0243), while clearance of injected isotope was similar in ffe/+ and +/+ mice. These values were compared to intestinal absorption of (59)Fe, which was significantly reduced in ffe/+ mice (8.751 vs. 3.978% dose; P = 0.0458). The influence of the ffe mutation was examined in dopaminergic SH-SY5Y cells and human embryonic HEK293T cells. While expression of wild-type Fpn reversed Mn-induced cytotoxicity, ffe mutant H32R failed to confer protection. These combined results demonstrate that Fpn plays a central role in Mn transport and that flatiron mice provide an excellent genetic model to explore the role of this exporter in Mn homeostasis. -

Keywords: hepcidin; iron metabolism; manganese transport.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biological Transport, Active
  • Cation Transport Proteins / deficiency*
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism
  • Cell Line
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism
  • HEK293 Cells
  • Homeostasis
  • Humans
  • Intestinal Absorption
  • Iron / deficiency
  • Iron / metabolism
  • Manganese / metabolism*
  • Manganese / toxicity
  • Mice
  • Mice, Mutant Strains
  • Models, Animal
  • Models, Genetic
  • Mutation, Missense
  • Neurotoxins / metabolism
  • Neurotoxins / toxicity

Substances

  • Cation Transport Proteins
  • Neurotoxins
  • metal transporting protein 1
  • Manganese
  • Iron