Characterization of 2,3-bis(chloromethyl)-1,4-naphthoquinone induced mitochondrial swelling

Mitochondrial swelling induced by 2,3-bis(chloromethyl)-1,4-naphthoquinone (CMNQ) was found to be a non-energy linked, oxygen and sulfhydryl-dependent, substrate-independent, osmotic process, that lacks cation specificity. Swelling was inhibited by cysteine and DTNB, and the CMNQ induced swelling resulted in a decrease in mitochondrial reactive sulfhydryl groups; thus, mitochondrial sulfhydryl interaction was mandatory in the CMNQ swelling process. The non-enzymatic reaction of CMNQ with cysteine but not cystine resulted in the consumption of oxygen, implicating sulfhydryl redox activity in the swelling process. High levels of tocopherol and histidine depressed the CMNQ induced swelling, suggesting that free radicals and singlet oxygen are important in the CMNQ induced swelling process.These findings support the proposition that CMNQ interacts with mitochondrial reductase systems and sulfhydryl groups in such a way as to generate superoxide radical which subsequently may dismute to H₂O₂ and produce ·OH and possibly singlet oxygen. These toxic oxygen species may be responsible for the CMNQ-promoted sulfhydryl depletion and mitochondrial swelling.