Pathological mitochondrial copper overload in livers of Wilson's disease patients and related animal models

Abstract

In Wilson's disease (WD) and related animal models, liver mitochondria are confronted with an increasing copper burden. Physiologically, the mitochondrial matrix may act as a dynamic copper buffer that efficiently distributes the metal to its copper-dependent enzymes. Mitochondria are the first responders in the event of an imbalanced copper homeostasis, as typical changes of their structure are among the earliest observable pathological features in WD. These changes are due to accumulating copper in the mitochondrial membranes and can be reversed by copper-chelating therapies. At the early stage, copper-dependent oxidative stress does not seem to occur. On the contrary, however, when copper is massively deposited in mitochondria, severe structural and respiratory impairments are observed upon disease progression. This provokes reactive oxygen species and consequently causes the mitochondrial membranes to disintegrate, which triggers hepatocyte death. Thus, in WD mitochondria are prime targets for copper, and the excessive copper burden causes their destruction, subsequently provoking tissue failure and death.

Methanobactin reverses acute liver failure in a rat model of Wilson disease

“…The early hepatocellular phenotype in these animals is characterized by increased mitochondrial copper accumulation, provoking progressive alterations of their structure (18). A similar mitochondrial phenotype has been reported in WD patients and in other WD animal models (19)(20)(21)(22). In Atp7b -/-rats, mitochondrial changes could be reversed by several weeks of treatment with copper chelators.…”

“…On the contrary, excess mitochondrial copper loads and severe mitochondrial destruction were observed at the onset of hepatitis in the LEC and Atp7b -/-rats (18), arguing for the pivotal need to reverse this mitochondrial copper overload. Given that mitochondrial Cco, the intermembrane Cu/Zn SOD, and the mitochondrial copper chaperones present with exceptionally low Cu 1+ dissociation constants, there is a considerable driving force of copper into mitochondria (20,44). Consequently, efficient mitochondrial copper removal may be achieved by compounds with high copper affinities.…”

Interactions of copper and thermal stress on mitochondrial bioenergetics in rainbow trout, Oncorhynchus mykiss

“…Mechanistically, the increased proton leak observed here could result from temperature-induced changes in membrane permeability and/or activity of the proteins that mediate this process (Moyes and Ballantyne, 2011;Fields, 2011;Hazel, 1995). Copper also can modify these proteins and membranes through oxidative stress and binding to thiols (Garcia et al, 2000;Letelier et al, 2005;Zischka and Lichtmannegger, 2014) as well as by inducing MPTP (Belyaeva et al 2011;Reddy et al, 2008;Zischka and Lichtmannegger, 2014; this study), thereby increasing proton leak.…”

Redox-implications associated with the formation of complexes between copper ions and reduced or oxidized glutathione

“…over-exposure to copper) or genetically-defined conditions (e.g. Wilson's disease), such mechanisms can fail or be overridden, leading to the accumulation of potentially toxic concentrations of copper [11][12][13][14]. Secondary to the intracellular accumulation of copper, its toxicity is likely to arise from the occurrence of trace amounts of free copper ions, as the latter species have a well-established potential to induce damage to biological targets [15].…”