Fig. 3.

Oxidative stress–initiated metabolism of mitochondrial NAD by PARP-1. Inhibition of mitochondrial respiration by cyanide (CN) stimulates production of superoxide ( ${\text{O}}_2^{-}$), which reacts with nitric oxide (NO·), forming peroxynitrite (ONOO⁻), In the absence of reducing power to maintain sulfhydryl groups in a reduced redox state, peroxynitrite leads to net sulfhydryl oxidation. This oxidized redox state together with elevated intramitochondrial Ca²⁺ results in activation of the cyclophilin D (CyD)–dependent and cyclosporin A (CsA)-inhibitable permeability transition pore (PTP). Release of mitochondrial pyridine nucleotides through the PTP promotes further NAD metabolism by cytosolic/nuclear PARP-1. Activation of mitochondrial PARP may also contribute to NAD degradation. The presence of either exogenous or endogenous pyruvate helps to maintain a reduced mitochondrial redox state, thereby conferring protection against both PTP and PARP-1 activation.