NAD, depletion

Pillai J, Isbatan A, Imai S-I, Gupta M (2005) Poly(ADP-ribose) Polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD depletion and reduced Sir2a deacetylase activity. J Biol Chem 280 43121-43130... 

Ca2+ cycling into and out of the mitochondria leads to NAD depletion and a fall in ATP. The entry of Ca2+ into the mitochondria dissipates the potential difference across the mitochondrial membranes and so inhibits the function of ATP synthase, which relies on the charge difference across the membrane (Fig. 6.13 and 7.60). Export of Ca2+ from the mitochondrial matrix may occur and be stimulated by some chemicals. However, this will lead to repeated cycling, which damages the membrane and further compromises ATP synthesis. The export of Ca2+ also uses up ATP as a result of the Ca2+ ATPases involved. Hence ATP levels fall. 

ROS play a critical role in initiation of apoptosis through changes in mitochondrial permeability, andpoly(ADP-ribose) polymerase (PARP) activation. These processes provide additional mechanisms for oxidative damage in acute neural trauma and neurodegenerative diseases (Warner et al., 2004). PARP activation is accompanied by the depletion of nicotinamide adenine dinucleotide, NAD. Depletion of NAD leads to depletion of ATP, which in turn promotes neuronal cell death (Zhang etal., 1994 Ishikawaetal., 1999). 

Martens, M.E., Smith, W.J. (2008). The role of NAD depletion in the mechanism of sulfur mustard-induced metabolic injury. J. Toxicol. Cutan. Ocul. Toxicol. 27 41-53. 

Clark RS, et al. Local administration of the poly(ADP-ribose) 160. polymerase inhibitor INO-1001 prevents NAD- -depletion and improves water maze performance after traumatic brain injury 161. in mice. J. Neurotrauma 2007 24 1399-1405. 

Stubberfield CR, Cohen GM. 1986. NAD+ depletion and cytotoxicity in isolated hepatocytes. Biochem. Pharmacol. 37 3967-74... 

Hoyt DG, Lazo JS. 1993. NAD depletion after in vitro exposure of murine lung slices to bleomycin. Biochem. Pharmacol. 46 1819-24... 

PARP inhibitors can be used to maintain cellular energetics. They do this by preventing NAD depletion, which helps prevent ATP depletion. In addition, inhibited PARP remains bound to DNA and is less vulnerable to the actions of caspase-3. This helps prevent necrosis and apoptosis. 

Lin P, Bernstein A and Vaughan FL (1994). Failure to observe a relationship between bis-(B-chloroethyl)sulphide-induced NAD depletion and cytotoxicity in the rat kerinocyte culture. J Toxicol Environ Health, 42, 393-405. 

Alano CC, Ying W, Swanson RA. Poly(ADP-ribose) polymerase-1 mediated cell death in astrocytes requires NAD depletion and mitochondrial permeability transition. J Biol Chem 2004 279 18895-18902. 

Thies RL, Autor AP. Reactive oxygen injury to cultured pulmonary artery endothelial cells Mediation by poly(ADP-ribose) polymerase activation causing NAD depletion and altered energy balance. Arch Biochem Biophys 1991 286 353-63. 

Radons J, Heller B, Burkle A et al. Nitric oxide toxicity in islet cells involves polyfADP-ribose) polymerase activation and concomitant NAD+ depletion. Biochem Biophys Res Commun 1994 199 1270-7. 

We have also experimentally manipulated ADP-ribosylation by partially depleting the cells of their NAD" content, by nicotinamide starvation. The NAD -depleted... 

Wielckens K, Schmidt A, George E, Bredehorst R, Hilz H (1982) DNA fragmentation and NAD depletion. Their relation to the turnover of endogenous mono(ADP-ribosyl) and poly(ADP-ribosyl) proteins. J Biol Chem 257 12872-12877... 

Table 3. Effect of acute heat shock on NAD depletion...

Treatment No addition NAD depletion pmol/10 cells 34mWMNNG ... 

We propose that conditions altering the availability of NAD may be signaled to chromatin by the intermediacy of poly(ADP-ribose) (Fig. 2). The question is whether this signal operates imder physiological conditions. Some reports have provided direct evidence that NAD- depletion forced upon cells by incubation in nicotinamide-free medium, arrests poly(ADP-ribose) synthesis (5) and drastically alters chromatin functions (5-7). For example, DNA repair in response to a chemical carcinogen was arrested under these conditions, but could be reestablished with nicotinamide, which restored normal intracellular NAD- and poly(ADP-ribose) levels (5). Similarly, myoblast differentiation was reversibly inhibited either by nicotinamide starvation or by selective inhibition of poly(ADP-ribose) polymerase (7). These results illustrate that nutritional manipulation of... 

Fig. 2. Bidirectional signaling through poly(ADP-ribose). A and B, suicidal NAD depletion in the presence of excessive amounts of DNA strand breaks as j oposed by Berger and associates C and D, reverse signaling of NAD availability through poly(ADP-ribose) (this report, 4). For further discussion see text.

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