Subcellular Compartmentation of NAD and Its Metabolism

The cellular NAO concentration has been measured many times in a variety of tissues and cells and can generally be stated to be in tbe low (sub)millimolar range. It has to be noted, however, that most of the dinudeoride is protein-bound in vivo. Additional lariablity has been observed with r ard to the ratio of NADVNADH, even at testing state. Clearly, this ratio also depends on the metabolic conditions. 

On the other hand, the pathway of mitochondrial NAD generation is still obscure. NMNAT aaivity in mitochondria has been reported and a third human NMNAT isoform could possibly be localised within these organelles. However, it is unknown how NMN would enter the mitochondria or be formed therein. Fortunately, there is at least no question as to how the second substrate of NMNAT, namely ATP, is generated within mitochondria. 

The observed massive NAD consumption following extensive DNA damage has promoted the view that PARPl may serve as a suicide device to exclude cell survival by eliminating a vital energy carrier (the suicide hypothesis , see ref. 42 for a review). In fact such an interpretation seemed even more appealing when it turned out that NMNATl is also located within the 

Nelsestuen GL, Kirkwood S. The mechanism of action of the enzyme diphosphoglucose 4-epime-rase. J Biol Chem 1971 246 7533-7543. 

Berger F, Ramirez-Herndndez MH., Ziegler M. The new life of a centenarian Signalling functions of NAD(P). Trends Biochem Sci 2004 29 111-118. 

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