AbstractThe co-enzyme nicotinamide adenine dinucleotide (NAD+) is an essential co-factor for cellular energy generation in mitochondria as well as for DNA repair mechanisms in the cell nucleus involving NAD+-consuming poly (ADP-ribose) polymerases (PARPs). Mitochondrial function is compromised in animal models of Parkinson’s disease (PD) associated with PARKIN mutations. Here, we uncovered alterations in NAD+salvage metabolism inDrosophila parkinmutants. We show that a dietary supplementation with the NAD+precursor nicotinamide rescues mitochondrial function and is neuroprotective. Further, by mutatingParpinparkinmutants, we show that this increases levels of NAD+and its salvage metabolites. This also rescues mitochondrial function and suppresses dopaminergic neurodegeneration. We conclude that strategies to enhance NAD+levels by administration of dietary precursors or the inhibition of NAD+-dependent enzymes, such as PARP, that compete with mitochondria for NAD+could be used to delay neuronal death associated with mitochondrial dysfunction.