Fig. 1.

Oxidative stress–initiated metabolism of cytosolic NAD by PARP-1. Superoxide ( ${\text{O}}_2^{-}$), produced from mitochondria and other sources, reacts with nitric oxide (NO·), producing peroxynitrite (ONOO⁻), a powerful oxidant of DNA and proteins. DNA oxidation activates poly(ADP-ribose) polymerase 1 (PARP-1), which metabolizes NAD to nicotinamide and poly(ADP-ribosylated) (PAR) proteins. The fall in NAD can inhibit the glycolytic production of pyruvate, a major source of fuel for oxidative phosphorylation (OxPhos). Resynthesis of NAD from nicotinamide is dependent on the energy supplied by ATP. PARP-1 can be alternatively activated by exposing cells to MNNG and inhibited by exposure to DPQ.