Abstract
Previous phenotyping of glucose homeostasis and insulin secretion in a mouse model of hereditary hemochromatosis (Hfe(-/-)) and iron overload suggested mitochondrial dysfunction. Mitochondria from Hfe(-/-) mouse liver exhibited decreased respiratory capacity and increased lipid peroxidation. Although the cytosol contained excess iron, Hfe(-/-) mitochondria contained normal iron but decreased copper, manganese, and zinc, associated with reduced activities of copper-dependent cytochrome c oxidase and manganese-dependent superoxide dismutase (MnSOD). The attenuation in MnSOD activity was due to substantial levels of unmetallated apoprotein. The oxidative damage in Hfe(-/-) mitochondria is due to diminished MnSOD activity, as manganese supplementation of Hfe(-/-) mice led to enhancement of MnSOD activity and suppressed lipid peroxidation. Manganese supplementation also resulted in improved insulin secretion and glucose tolerance associated with increased MnSOD activity and decreased lipid peroxidation in islets. These data suggest a novel mechanism of iron-induced cellular dysfunction, namely altered mitochondrial uptake of other metal ions.
Highlights
Hereditary hemochromatosis (HH) is a common autosomal recessive disorder of iron metabolism [1,2]
Because the insulin secretion abnormalities in iron-overloaded Hfe–/– mice are suggestive of mitochondrial dysfunction [11], we assessed mitochondrial function in Hfe–/– mice and wild type controls
Mitochondrial function was analyzed by measuring the rates of oxygen consumption utilizing two substrates which serve as functional markers for electron transport complexes I and II, respectively
Summary
Hereditary hemochromatosis (HH) is a common autosomal recessive disorder of iron metabolism [1,2]. Patients with HH are characterized by excessive intestinal absorption of dietary iron leading to systemic iron overload in multiple organs which may result in cirrhosis, diabetes, and cardiac failure [1,5,6,7]. This is associated with reductions in mitochondrial oxygen consumption, the activities of mitochondrial manganese-dependent superoxide dismutase (MnSOD), and copper-dependent cytochrome c oxidase (CCO) This mitochondrial dysfunction is reversible with manganese supplementation, which normalizes lipid peroxidation and MnSOD activity, and leads to enhanced insulin secretory capacity and improved glucose tolerance in Hfe–/– mice
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