Microbial peptide de-coppers mitochondria: implications for Wilson disease

Abstract

The severe liver pathology of untreated Wilson disease (WD) is associated with massive copper overload caused by mutations in a liver-specific copper-transporting ATPase, ATP7B. While early, presymptomatic detection and chelation with conventional copper-binding molecules enables effective and life-saving treatment, liver transplantation is the sole option currently available for those with advanced disease. In this issue of the JCI, Lichtmannegger, Leitzinger, and colleagues delineate the therapeutic effect of methanobactin (MB), a potent bacterial copper-binding protein, at three late stages of disease in a WD rat model. Their results suggest that a formal clinical trial of MB in human subjects with severe hepatic pathology caused by WD would be rational.

Figure 1. Hepatocyte copper depletion by MB in late-stage WD.

Top: Cartoon of the human liver, with details of the portal triad architecture. In late-stage WD, MB (lavender diamonds) administered by i.v. infusion would be taken up by diseased hepatocytes and enter copper-engorged mitochondria (left panel), followed by chelation of copper (blue circles) and exodus from diseased mitochondria of MB-copper complexes destined for biliary excretion (middle panel). The preclinical rat model described by Lichtmannegger, Leitzinger, and colleagues (14) predicts efficient and effective removal of mitochondrial copper by MB, with restoration of normal mitochondrial structure (right panel).