Nitric oxide, mitochondria, and cell death.

NO or its derivatives (reactive nitrogen species: RNS) have three types of actions on mitochondria: 1) reversible inhibition of mitochondrial respiration at cytochrome oxidase by NO, and irreversible inhibition at multiple sites by RNS; 2) stimulation of mitochondrial production of superoxide, hydrogen peroxide, and peroxynitrite by NO; and 3) induction of mitochondrial permeability transition (MPT) by RNS. Similarly there are three main roles of mitochondria in NO-induced cell death: a) NO inhibition of respiration can induce necrosis (or excitotoxicity in neurons) and inhibit apoptosis if glycolysis is insufficient to compensate, b) RNS- or oxidant-induced signal transduction or DNA damage may activate the mitochondrial pathway to apoptosis, and c) RNS-induced MPT may induce apoptosis or necrosis.