Fig. 14.

Crosstalk between different sources of RONS: mitochondria, NADPH oxidase (NOX), xanthine oxidase (XO) and uncoupled NOS. XO originates from oxidative stress-mediated conversion of the xanthine dehydrogenase via oxidation of critical thiols in cysteine535/992. NOS (mainly eNOS) are uncoupled upon oxidative depletion of BH4, S-glutathionylation (-SSG), adverse phosphorylation by protein kinase C (PKC) and other redox switches [535]. Mitochondrial O₂^•‾/H₂O₂ formation is triggered by oxidative stress from all ROS sources (including other damaged/activated mitochondria) via redox-activation of PKC, mitogen-activated protein kinases (MAPK), other kinase pathways and potential involvement of redox-sensitive mtK_ATP with subsequent p66^Shc, monoamine oxidase (MAO), respiratory complex activation or impairment of mitochondrial antioxidant defense [352]. Mitochondrial O₂^•‾/H₂O₂ is released to the cytosol via mitochondrial pores and channels (e.g. redox-sensitive mPTP, inner membrane anion channel (IMAC) or aquaporins) or by diffusion due to increased mitochondrial permeability under pro-inflammatory conditions. In the cytosol these species (along with released calcium) cause activation of redox-sensitive PKC and tyrosine kinases (cSrc) with subsequent activation of NOX and amplification of the cellular oxidative stress [410]. Adapted from Ref. [352] with permission.