Figure 5. Possible mechanisms of mitochondrial redox signalling.

The production of H₂O₂ from mitochondria is a potential redox signal. H₂O₂ generated by mitochondria can reversibly alter the activity of proteins with critical protein thiols by modifying them to intra- or inter-protein disulfides, or to mixed disulfides with GSH. These modifications can occur on mitochondrial, cytosolic or nuclear enzymes, carriers or transcription factors, transiently altering their activities. The change in activity can be reversed by reducing the modified protein thiol by endogenous thiol reductants such as GSH or thioredoxin. As the extent of H₂O₂ production from mitochondria will depend on factors such as Δp or the redox state of the NADH pool, it can act as a retrograde signal to the rest of the cell, reporting on mitochondrial status. This signal can then lead to the short-term modification of, for example, pathways supplying substrates to the mitochondria. Alternatively, longer-term modifications can occur through modifying redox-sensitive transcription factors that adjust the production of mitochondrial components. In addition, external signals may modify O₂^•− production by the respiratory chain by post-translational modification. Alteration of the activity of mitochondrial peroxidases could also modulate H₂O₂ efflux from mitochondria to the rest of the cell. It is also possible that secondary redox signals, such as lipid peroxidation products derived from H₂O₂, could act as secondary redox signals.