Schematic representation of the inhibitory effects of NO and ONOO- on the ETC, enzymes of the tricarboxylic cycle and antioxidant enzymes. NO and peroxynitrite inhibit the mitochondrial respiration via different mechanisms: NO itself causes selective, rapid, potent, but readily reversible inhibition of cytochrome oxidase and increased production of RNS within the intermembrane space. On the other hand, excessive levels of peroxynitrite and other RNS leads to slow, weak non-selective, but essentially irreversible inhibition of a wide range of mitochondrial components. Peroxynitrite inhibits Complex I, Complex II, cytochrome oxidase ATP synthase, MnSOD, aconitase, creatine kinase, and a plethora of other proteins playing an essential role in energy production. In addition, peroxynitrite is a potent oxidant capable of inducing peroxidation of mitochondrial membrane lipid components, hence increasing membrane permeability and disrupting the potential difference between the inner and outer membrane and inducing mitochondrial membrane transition. Inhibition of ATP production and electron chain dysfunction leads to the production of ever increasing production of ROS and RNS leading to a vicious circle culminating in eventual bioenergetic failure and often cellular necrosis or apoptosis.