Effects of Iron Overload on the Activity of Na,K-ATPase and Lipid Profile of the Human Erythrocyte Membrane

Abstract

Iron is an essential chemical element for human life. However, in some pathological conditions, such as hereditary hemochromatosis type 1 (HH1), iron overload induces the production of reactive oxygen species that may lead to lipid peroxidation and a change in the plasma-membrane lipid profile. In this study, we investigated whether iron overload interferes with the Na,K-ATPase activity of the plasma membrane by studying erythrocytes that were obtained from the whole blood of patients suffering from iron overload. Additionally, we treated erythrocytes of normal subjects with 0.8 mM H2O2 and 1 μM FeCl3 for 24 h. We then analyzed the lipid profile, lipid peroxidation and Na,K-ATPase activity of plasma membranes derived from these cells. Iron overload was more frequent in men (87.5%) than in women and was associated with an increase (446%) in lipid peroxidation, as indicated by the amount of the thiobarbituric acid reactive substances (TBARS) and an increase (327%) in the Na,K-ATPase activity in the plasma membrane of erythrocytes. Erythrocytes treated with 1 μM FeCl3 for 24 h showed an increase (132%) in the Na,K-ATPase activity but no change in the TBARS levels. Iron treatment also decreased the cholesterol and phospholipid content of the erythrocyte membranes and similar decreases were observed in iron overload patients. In contrast, erythrocytes treated with 0.8 mM H2O2 for 24 h showed no change in the measured parameters. These results indicate that erythrocytes from patients with iron overload exhibit higher Na,K-ATPase activity compared with normal subjects and that this effect is specifically associated with altered iron levels.

Acute Free-Iron Exposure Does Not Explain the Impaired Haemorheology Associated with Haemochromatosis

“…Our direct measurement of RBC deformability following incubation with FeCl 3 extends the recent finding that FeCl 3 modulated Na,K ATPase of RBC, which presumably would influence cell volume, ion content, and thus would be predicted to determine RBC deformability [ 20 ]. It is possible that increased Na,K ATPase activity in response to FeCl 3 may be offset by opposing factors during incubation studies (e.g., cell ageing; temperature effects etc) and thus result in no net-functional change to RBC deformability; however, it is also likely that differences in incubation period of the present study (60 min) and that of Sousa et al, [ 20 ] may explain, in part, these discordant findings. The fact that we did not observe impaired haemorheology with acute iron incubation in vitro does not discount the possibility that chronic exposure to iron, or its interaction with other [plasma?]…”

“…Iron has a dose-dependent role in haemorheological health: while conditions classically associated with iron-overload are associated with impaired haemorheology, iron supplementation may correct haemorheological parameters in iron-deficient anaemia [ 18 , 19 ]. The lipid bilayer of RBC membranes is susceptible to oxidative damage from free radicals, and the Na,K ATPase of RBC are modulated by FeCl 3 [ 20 ], thus elevated free iron may explain altered haemorheology through promotion of reactive species generation [ 21 , 22 ] as well as altered cell volume modulated via ion channels [ 20 ]. In the present study, HFE-HH was associated with a decreased elongation index (i.e., RBC deformability) at low-to-moderate shear stress and an increased (i.e., impaired) SS 1/2 : these findings collectively indicate that RBC from HFE-HH patients were less deformable/more rigid than controls.…”

The molecular machinery of regulated cell death

“…17 At the molecular level, Tat-Beclin 1–induced autosis can be inhibited by blocking upstream Na + /K + -ATPase, a plasma pump linking ion homeostasis and ER stress. 17 Interestingly, iron overload stimulates Na + /K + -ATPase activity in the human erythrocyte membrane, 237 which may lead to ferroptosis. However, the exact relationship between autosis and ferroptosis remains to be determined.…”

Overexpression of Sideroflexin1 (SFXN1) Predicts Worse Overall Survival in Lung Adenocarcinoma

“…also discovered SFXN1, a mitochondria iron transporting protein, carries the overload free iron to mitochondria, causing the impairment of mitochondria and the subsequent cardiomyocytes hypertrophy in the long run [21]. Additionally, Sousa L and colleagues demonstrated that iron overload patients exhibit higher ATPase activity in their erythrocytes [22]. Accordingly, SFXN1 may promote the transportation of iron by virtue of enhancing the ATPase activity although further experimental validation is required.…”