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

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.