A nuclear SIRT1 mechanism for delaying NAD-ATP depletion through inhibition of PARP-1 is presented

A nuclear SIRT1 mechanism for delaying NAD-ATP depletion through inhibition of PARP-1 is presented. The NAD salvage pathway uses nicotinamide (NAM) as a substrate. NAMPT1 converts nicotinamide (NAM) to nicotinamide mononucleotide (NMN) which via nicotinamide adenylyl-transferase (NMNAT) gets converted to NAD. Both of these processes require ATP. Reactive oxygen/nitrogen species (R(O/N)S) causing DNA damage causes activation of PARP-1, which leads to NAD depletion as NAD is used as a substrate in the polymerization reaction. The salvage pathway is simultaneously activated by (R(O/N)S), which leads to a futile NAD-recycling process that ultimately depletes ATP. Similar lesser characterized ATP depleting pathways are predicted specifically in axonal cytosol and mitochondria where NMNAT2 and NMNAT3 enzymes have been colocalized respectively with Sirtuin and PARP family members. R(O/N)S cause damage to DNA, which activates PARP-1 leading to NAD depletion through use of NAD as a substrate to generate poly(ADP)ribose, PAR (1). Nicotinamide (NAM) is used by nicotinamide phosphoribosyltransferase (NAMPT) to make nicotinamide mononucleotide (NMN). This is then converted to NAD via nicotinamide nucleotide adenylyltransferase 1 (NMNAT1), part of the genomic triplication responsible for the slow Wallerian degeneration mouse (Wlds) phenotype. The NAD salvage pathway repeatedly uses ATP to replenish NAD (2). The NAD-dependent mitochondrial deacetylase, SIRT3, functions as a master regulator of ATP levels. Under ischemic conditions NAD is required to maintain production of ATP from anaerobic glycolysis. The increased salvage pathway efficiency of the Wlds mouse is probably able to provide NAD to maintain ATP generation by anaerobic glycolysis during oxidative stress (3). Otherwise ATP can be supplied via oxidative phosphorylation (4). The futile cycle continues until PAR formation triggers AIF-dependent apoptosis or ATP stores are so depleted that necrosis happens (5). PARP-1 activity can be inhibited directly (e.g. minocycline and PJ-34 are nanomolar affinity inhibitors) or indirectly through activation of SIRT-1 (e.g. resveratrol; 6). Either PARP-1 inhibitory approach can significantly delay NAD and ATP depletion similar to the Wlds mouse. Alternatively pharmacological administration of NAD or precursors can help prevent deficiencies. All of the pharmacological approaches described here have been shown to ameliorate EAE pathogenesis in published reports. Neurons are particularly susceptible to depletion of NAD owing to their apparent lack of a fully functional salvage pathway (see text).

Publication

The Importance of NAD in Multiple Sclerosis. () W. Todd Penberthy, et al. Curr Pharm Des. ;15(1):64-99. Figure: F2. All organisms Drosophila melanogaster Homo sapiens

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