Clioquinol (CQ), a once popular antibiotic, was used to inhibit the growth of 
microorganisms. Recently, CQ and its analog PBT2 have shown encouraging effects 
in the animal and clinical trials for Alzheimer's disease (AD). However, the 
mechanism by which this class of molecules works remains controversial. In this 
work, we used the yeast Saccharomyces cerevisiae as a model to study how CQ 
affects molecular and cellular functions and particularly, copper, iron, and 
zinc homeostasis. We observed a CQ-induced inhibition of yeast growth, which 
could be slightly relieved by supplementation of copper or iron. Microarray 
results indicated that yeast cells treated with CQ sense a general deficiency in 
metals, despite elevated total cellular contents of copper and iron. Consistent 
with this, reduced activities of some metal-sensitive enzymes were observed. 
Intriguingly, CQ can increase the SOD1 activity, likely through Ccs1's 
accessibility to CQ-bound copper ions. Further studies revealed that CQ 
sequestrates copper and iron at the cellular membrane, likely the plasma 
membrane, resulting overall metal accumulation but cytosolic metal depletion. 
CQ's effects on metal-sensitive metalloenzymes were also verified in mammalian 
cell line SH-SY5Y. Together, our results revealed that CQ can regulate metal 
homeostasis by binding metal ions, resulting the cell sensing a state of 
deficiency of bioavailable metal ions while simultaneously increasing available 
metals to SOD1 (via Ccs1) and possibly some other metalloproteins that can 
access CQ-bound metals. We hope this regulation of metal homeostasis may be 
helpful in explaining the therapeutic effects of CQ used in disease treatment.