Clioquinol (Quinoform) was extensively administered to treat indigestion and diarrhea in the mid-1900s. However, it was withdrawn from the market in Japan because its use was epidemiologically linked to an increase in the incidence of subacute myelo-optic neuropathy (SMON). SMON is characterized by the subacute onset of sensory and motor disturbances in the lower extremities with occasional visual impairments, which are preceded by abdominal symptoms. The underlying mechanisms of clioquinol toxicity, however, have not been elucidated in detail. We previously reported that clioquinol induced oxidation of the copper chaperone ATOX1, leading to the impairment of the functional maturation of a copper-dependent enzyme dopamine-β-hydroxylase and the inhibition of noradrenaline biosynthesis. Effects of clioquinol on expression levels of other copper-related proteins were investigated. Quantitative PCR demonstrated that clioquinol decreased mRNA levels of SCO1 and SCO2, copper chaperones for mitochondrial respiratory chain complex IV (cytochrome c oxidase), and of COX18, a membrane insertase of a complex IV component. In clioquinol-treated cells, the assembly and activity of complex IV were suppressed. Thus, clioquinol was suggested to suppress ATP synthesis through this pathway, leading to neuronal cell death.