Copper Cytotoxicity: Cellular Casualties of Noncognate Coordination Chemistry

Copper (Cu) is an essential micronutrient for cells, but in excess it is cytotoxic. How Cu is cytotoxic is the subject of recent work by L. Zuily, N. Lahrach, R. Fassler, O. Genest, et al. (mBio 13:e03251-21, 2022, https://doi.org/10.1128/mbio.03251-21). Using Escherichia coli as the model cell, the work shows that anoxic cells accumulate larger amounts of Cu than do oxic cells. Accordingly, Cu is more cytotoxic under anoxic than oxic conditions. The work further shows that Cu cytotoxicity in anoxic bacteria is associated with increased intracellular protein aggregation. The mechanistic details remain as open questions, but these questions highlight that a fundamental understanding of Cu speciation and availability in cells is essential to uncover the cellular consequences of Cu cytotoxicity.