Coenzyme Q10 and nicotinamide nucleotide transhydrogenase: Sentinels for mitochondrial hydrogen peroxide signaling

Mitochondria use hydrogen peroxide (H2O2) as a mitokine for cell communication. H2O2 output for signaling depends on its rate of production and degradation, both of which are strongly affected by the redox state of the coenzyme Q10 (CoQ) pool and NADPH availability. Here, we propose the CoQ pool and nicotinamide nucleotide transhydrogenase (NNT) have evolved to be central modalities for mitochondrial H2O2 signaling. Both factors play opposing yet equally important roles in dictating H2O2 availability because they are connected to one another by two central parameters in bioenergetics: electron supply and Ap. The CoQ pool is the central point of convergence for electrons from various dehydrogenases and the electron transport chain (ETC). The increase in Ap creates a significant amount of protonic backpressure on mitochondria to promote H2O2 genesis through CoQ pool reduction. These same factors also drive the activity of NNT, which uses electrons and the Ap to eliminate H2O2. In this way, electron supply and the magnitude of the Ap manifests as a redox connection between the two sentinels, CoQ and NNT, which serve as opposing yet equally important forces required for budgeting H2O2. Taken together, CoQ and NNT are sentinels linked through mitochondrial bioenergetics to manage H2O2 availability for interorganelle and intercellular redox signaling.