Severe dysfunction of respiratory chain and cholesterol metabolism in Atp7b−/− mice as a model for Wilson disease

Abstract

Wilson disease (WD) is caused by mutations of the WD gene ATP7B resulting in copper accumulation in different tissues. WD patients display hepatic and neurological disease with yet poorly understood pathomechanisms. Therefore, we studied age-dependent (3, 6, 47weeks) biochemical and bioenergetical changes in Atp7b(-/-) mice focusing on liver and brain. Mutant mice showed strongly elevated copper and iron levels. Age-dependently decreasing hepatic reduced glutathione levels along with increasing oxidized to reduced glutathione ratios in liver and brain of 47weeks old mice as well as elevated hepatic and cerebral superoxide dismutase activities in 3weeks old mutant mice highlighted oxidative stress in the investigated tissues. We could not find evidence that amino acid metabolism or beta-oxidation is impaired by deficiency of ATP7B. In contrast, sterol metabolism was severely dysregulated. In brains of 3week old mice cholesterol, 8-dehydrocholesterol, desmosterol, 7-dehydrocholesterol, and lathosterol were all highly increased. These changes reversed age-dependently resulting in reduced levels of all previously increased sterol metabolites in 47weeks old mice. A similar pattern of sterol metabolite changes was found in hepatic tissue, though less pronounced. Moreover, mitochondrial energy production was severely affected. Respiratory chain complex I activity was increased in liver and brain of mutant mice, whereas complex II, III, and IV activities were reduced. In addition, aconitase activity was diminished in brains of Atp7b(-/-) mice. Summarizing, our study reveals oxidative stress along with severe dysfunction of mitochondrial energy production and of sterol metabolism in Atp7b(-/-) mice shedding new light on the pathogenesis of WD.

Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation

“…Previous reports indicated that a defected ATP7B, one of the major copper-delivery targets of Atox1, could lead to altered COX activity in mice 37 . We found that the activities of COX (units ml −1 ) in H1299 cells in the presence of DC_AC50 are significantly lower than those of the control (Fig.…”

The importance of the excitatory amino acid transporter 3 (EAAT3)

“…The high metabolism of neurons produces a lot of oxidative stress, demanding a high-capacity system for maintaining the redox homeostasis. Intracellular Cys seems to be the rate-limiting factor for GSH synthesis in neurons (Griffith, 1999), and oxidative stress and altered GSH levels have been implicated in several diseases including multiple sclerosis, Wilson disease, Parkinson’s disease (PD), Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS) where protein redox state has been described in mechanisms of redox-regulated cell death, (Dringen, 2000, Uttara et al, 2009, Haider et al, 2011, Sauer et al, 2011, McBean et al, 2015). …”

The Role of Copper as a Modifier of Lipid Metabolism

“…These early changes in lipid metabolism are maintained throughout the course of the disease as indicated by the analysis of the mRNA levels and serum lipid profiles at the later stages of the disease (80). Follow-up studies revealed that the sterol metabolism in a brain of young Atp7b-/-mice was also dysregulated, with cholesterol, 8-dehydrocholesterol, desmosterol, 7-dehydrocholesterol, and lathosterol all being highly increased (81,82). It should be noted that the main cholesterol-sensing pathway that involves proteolysis and nuclear localization of SREBP2 transcription factor is not impaired in Atp7b -/-hepatocytes (79).…”