Complex role of nicotinamide adenine dinucleotide in the regulation of programmed cell death pathways

Over the past few years, a growing body of experimental observations has led to the identification of novel and alternative programs of regulated cell death. Recently, autophagic cell death and controlled forms of necrosis have emerged as major alternatives to apoptosis, the best characterized form of regulated cell demise. These recently identified, caspase-independent, forms of cell death appear to play a role in the response to several forms of stress, and their importance in different pathological conditions such as ischemia, infection and inflammation has been recognized. The functional link between cell metabolism and survival has also been the matter of recent studies. Nicotinamide adenine dinucleotide (NAD(+)) has gained particular interest due to its role in cell energetics, and as a substrate for several families of enzymes, comprising poly ADP-ribose polymerases (PARPs) and sirtuins, involved in numerous biological functions including cell survival and death. The recently uncovered diversity of cell death programs has led us to reevaluate the role of this important metabolite as a universal pro-survival factor, and to discuss the potential benefits and limitations of pharmacological approaches targeting NAD(+) metabolism.