Coenzyme Q and nicotinamide nucleotide transhydrogenase: Sentinels for mitochondrial hydrogen peroxide signaling.

Mitochondria use hydrogen peroxide (HO) as a mitokine for cell communication. HO output for signaling depends on its rate of production and degradation, both of which are strongly affected by the redox state of the coenzyme Q (CoQ) pool and NADPH availability. Here, we propose the CoQ pool and nicotinamide nucleotide transhydrogenase (NNT) have evolved to be central modalities for mitochondrial HO signaling. Both factors play opposing yet equally important roles in dictating HO availability because they are connected to one another by two central parameters in bioenergetics: electron supply and Δp. The CoQ pool is the central point of convergence for electrons from various dehydrogenases and the electron transport chain (ETC). The increase in Δp creates a significant amount of protonic backpressure on mitochondria to promote HO genesis through CoQ pool reduction. These same factors also drive the activity of NNT, which uses electrons and the Δp to eliminate HO. In this way, electron supply and the magnitude of the Δp manifests as a redox connection between the two sentinels, CoQ and NNT, which serve as opposing yet equally important forces required for budgeting HO. Taken together, CoQ and NNT are sentinels linked through mitochondrial bioenergetics to manage HO availability for interorganelle and intercellular redox signaling.