FIG. 9.

Mitochondrial ROS and RNS production and targets of oxidative and nitrosative damage on mitochondrial proteins. Mitochondrial NO^• activity most likely arises from extramitochondrial NOS. Mitochondria-derived NOS (mNOS) may also play a role, but this remains unresolved. The ONOO⁻ (NO^• + O₂^•−) arising from the extramitochondrial sources or formed intramitochondrially undergoes reactions in the different mitochondrial compartments and small amounts may escape to the cytosol. As shown, ONOO^- targets several mitochondrial proteins important for normal physiological activity of the organelle. These include the ETC complexes, TCA cycle enzymes, and the scavenging system. The actions of RNS on these proteins could lead to mPTP opening and release of cytochrome c, or direct modulation of VDAC (voltage-dependent anion channel) and ANT (adenine nucleotide translocase) to release AIF (apoptosis inducing factor) and cytochrome c. S-nitrosation (SNO) play some regulatory role while nitration (NO₂) reactions appear to be more permanent modifications and strictly linked to oxidative damage (Sox). Reproduced and modified from Radi et al. (461). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).