Benzo[a]pyrene-derived quinones exploit mitochondrial electron transport to drive catalytic redox cycling and potent ROS amplification.

Benzo[a]pyrene (BP)-derived quinones are major oxidative metabolites of this ubiquitous environmental carcinogen, yet the mechanisms by which they generate reactive oxygen species (ROS) remain poorly understood. Here, we tested the hypothesis that BP-derived quinones exploit mitochondrial electron transport to undergo redox cycling and amplify ROS production. Using isolated mitochondria energized with either pyruvate/malate or succinate, we found that BP-1,6-quinone (BP-1,6-Q), BP-3,6-quinone (BP-3,6-Q), BP-6,12-quinone (BP-6,12-Q), and BP-7,8-quinone (BP-7,8-Q) stimulated potassium cyanide-resistant oxygen consumption, indicating active mitochondrial redox cycling. BP quinone redox cycling was accompanied by substantial production of superoxide and hydrogen peroxide, with BP-1,6-Q, BP-3,6-Q, and BP-6,12-Q exhibiting the greatest activity. Notably, BP-1,6-Q induced robust ROS generation at submicromolar concentrations, suggesting that mitochondria can serve as highly efficient amplifiers of BP quinone-mediated oxidative stress. Pharmacological dissection of the mitochondrial electron transport chain suggested complexes I and III as the principal sites supporting BP quinone redox cycling and ROS production, whereas the contributions of complexes II and IV were negligible. These findings indicate that BP-derived quinones exploit electron flow through mitochondrial complexes I and III to drive catalytic redox cycling and potent ROS amplification. This previously underappreciated mechanism provides a mechanistic link between BP metabolism, mitochondrial oxidative stress, and the pathogenesis of BP-associated toxicity.