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 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 H₂O₂ genesis through CoQ pool reduction. These same factors also drive the activity of NNT, which uses electrons and the Δp to eliminate H₂O₂. 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 H₂O₂. Taken together, CoQ and NNT are sentinels linked through mitochondrial bioenergetics to manage H₂O₂ availability for interorganelle and intercellular redox signaling.