title: The manganese superoxide dismutase Ala16Val dimorphism modulates iron accumulation in human hepatoma cells.
abstract: The Ala/16Val dimorphism incorporates alanine (Ala) or valine (Val) in the mitochondrial targeting sequence of manganese superoxide dismutase (MnSOD), modifying MnSOD mitochondrial import and activity. In alcoholic cirrhotic patients, the Ala-MnSOD allele is associated with hepatic iron accumulation and an increased risk of hepatocellular carcinoma. The Ala-MnSOD variant could modulate the expression of proteins involved in iron storage (cytosolic ferritin), uptake (transferrin receptors, TfR-1 and-2), extrusion (hepcidin), and intracellular distribution (frataxin) to trigger hepatic iron accumulation. We therefore assessed the Ala/Val-MnSOD genotype and the hepatic iron score in 162 alcoholic cirrhotic patients. In our cohort, this hepatic iron score increased with the number of Ala-MnSOD alleles. We also transfected Huh7 cells with Ala-MnSOD-or Val-MnSOD-encoding plasmids and assessed cellular iron, MnSOD activity, and diverse mRNAs and proteins. In Huh7 cells, MnSOD activity was higher after Ala-MnSOD transfection than after Val-MnSOD transfection. Additionally, iron supplementation decreased transfected MnSOD proteins and activities. Ala-MnSOD transfection increased the mRNAs and proteins of ferritin, hepcidin, and TfR2, decreased the expression of frataxin, and caused cellular iron accumulation. In contrast, Val-MnSOD transfection had limited effects. In conclusion, the Ala-MnSOD variant favors hepatic iron accumulation by modulating the expression of proteins involved in iron homeostasis.
authors.affiliation: UPRES EA3410, UFR SMBH, Université Paris 13, Bobigny, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Nahon
authors.forename: Nathalie
authors.initials: N
authors.lastname: Charnaux
authors.forename: Véronique
authors.initials: V
authors.lastname: Friand
authors.forename: Catherine
authors.initials: C
authors.lastname: Prost-Squarcioni
authors.forename: Marianne
authors.initials: M
authors.lastname: Ziol
authors.forename: Nicole
authors.initials: N
authors.lastname: Lièvre
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Trinchet
authors.forename: Michel
authors.initials: M
authors.lastname: Beaugrand
authors.forename: Liliane
authors.initials: L
authors.lastname: Gattegno
authors.forename: Dominique
authors.initials: D
authors.lastname: Pessayre
authors.forename: Angela
authors.initials: A
authors.lastname: Sutton