NQO1 protects against clioquinol toxicity

Area of Science:

• Neuroscience
• Toxicology
• Biochemistry

Background:

• Clioquinol (CQ) was withdrawn due to subacute myelo-optic neuropathy (SMON), but its mechanism and geographic restriction remain unclear.
• CQ and analogues are being reconsidered as neuroprotectants, necessitating an understanding of their toxicity.
• Previous toxicity studies failed to explain the Japan-specific SMON outbreak.

Purpose of the Study:

• To elucidate the mechanism of Clioquinol (CQ)-induced toxicity.
• To investigate the role of the antioxidant enzyme NQO1 in CQ toxicity.
• To explain the geographic restriction of SMON cases.

Main Methods:

• Small molecule screen for mitochondrial dysfunction in vitro.
• Cell line studies using isogenic cell lines with varying NQO1 expression.
• In vivo studies in zebrafish larvae and adults with and without NQO1.
• Pharmacological inhibition of NQO1 activity.

Main Results:

• CQ induces mitochondrial dysfunction, oxidative stress, and cell death.
• NQO1 expression protects against CQ toxicity in cell lines and zebrafish.
• CQ impairs vision in NQO1-deficient zebrafish larvae and causes systemic toxicity in adults with inhibited NQO1.
• Higher prevalence of inactivating NQO1 polymorphism in Japan correlates with SMON cases.

Conclusions:

• Oxidative stress mediated by NQO1 deficiency is the core mechanism of CQ toxicity.
• NQO1 status explains the geographic restriction of SMON to Japan.
• Ascertaining NQO1 levels is crucial for safe use of CQ or derivatives in neurodegenerative disease treatment.