Elevated cellular accumulation of endogenous and exogenous CoQ by altered intracellular trafficking.

Coenzyme Q (CoQ) is produced in the inner membrane of mitochondria, from where it is transported to other cellular membranes. Cellular CoQ levels drop when its synthesis is interrupted, indicating that it can be degraded or eliminated in some way by currently still uncharacterized mechanisms. Low cellular iron availability has been found to lower CoQ levels, at least in part by inhibiting the action of the CoQ biosynthetic enzyme COQ7. These findings prompted us to test the effect of elevated intracellular iron content on CoQ levels. In the mouse macrophage cell line RAW264.7, we found that supplementation with ferrous ions (Fe(2+)) boosts CoQ levels rapidly and reversibly. Iron loading also increases the cellular accumulation of exogenous CoQ(10) provided in the media. N-acetyl cysteine significantly attenuates the elevation of CoQ levels by iron, suggesting that the effect of iron is mediated by a redox mechanism, although overall cellular reactive oxygen species (ROS) levels were not affected. Treating RAW264.7 cells with the ROS-generator paraquat also dramatically increases CoQ, further pointing to a redox mechanism. No effect on the abundance of several COQ proteins was observed after iron or paraquat treatment, indicating that their effect on CoQ levels is unlikely to arise from altered mitochondrial CoQ synthesis. In contrast, we observed that targeting lysosome function also affects CoQ levels, suggesting that the effects we observe relate to degradation and/or recycling. Our study suggests that targeting these mechanisms could allow for new therapeutic options to boost cellular CoQ levels in patients.