Disturbances in mitochondrial bioenergetics and control quality and unbalanced redox homeostasis in the liver of a mouse model of mucopolysaccharidosis type II

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a lysosomal storage disease caused by mutations in the gene encoding the enzyme iduronate 2-sulfatase (IDS) and biochemically characterized by the accumulation of glycosaminoglycans (GAGs) in different tissues. It is a multisystemic disorder that presents liver abnormalities, the pathophysiology of which is not yet established. In the present study, we evaluated bioenergetics, redox homeostasis, and mitochondrial dynamics in the liver of 6-month-old MPS II mice (IDS⁻). Our findings show a decrease in the activity of α-ketoglutarate dehydrogenase and an increase in the activities of succinate dehydrogenase and malate dehydrogenase. The activity of mitochondrial complex I was also increased whereas the other complex activities were not affected. In contrast, mitochondrial respiration, membrane potential, ATP production, and calcium retention capacity were not altered. Furthermore, malondialdehyde levels and 2’,7’-dichlorofluorescein oxidation were increased in the liver of MPS II mice, indicating lipid peroxidation and increased ROS levels, respectively. Sulfhydryl and reduced glutathione levels, as well as glutathione S-transferase, glutathione peroxidase (GPx), superoxide dismutase, and catalase activities were also increased. Finally, the levels of proteins involved in mitochondrial mass and dynamics were decreased in knockout mice liver. Taken together, these data suggest that alterations in energy metabolism, redox homeostasis, and mitochondrial dynamics can be involved in the pathophysiology of liver abnormalities observed in MPS II.

We show a reduction in the content of proteins that indicate mitochondrial mass (VDAC and COX IV) and of proteins that regulate mitochondrial fission (Drp1) and fusion (OPA1) in the liver of MPS II mice. We also demonstrate lipid peroxidation, an increase in reactive oxygen species (ROS) levels and changes in non-enzymatic and enzymatic antioxidant defenses. The activities of complex I of the electron transport chain, α-ketoglutarate dehydrogenase, succinate dehydrogenase, and malate dehydrogenase were also altered in the liver of knockout mice.