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BBB Seminar: Mathias Ziegler

Generation and functions of subcellular NAD pools – key determinants of bioenergetic and signaling pathways

Mathias Ziegler
Department of Molecular Biology, University of Bergen

Nicotinamide adenine dinucleotide (NAD) is an essential redox carrier, whereas its degradation is a key element of a wide range of signaling pathways. The molecule is required for protein modifications (deacetylation, ADP-ribosylation) and as precursor of messenger molecules. NAD-mediated signaling does not merely modulate metabolic reactions. It is becoming increasingly clear that NAD-mediated regulatory processes are ubiquitously present throughout all organisms and that they participate in the control of fundamental cellular events including life span and cell cycle regulation, gene expression, DNA repair, cell differentiation, calcium signaling and apoptosis. In addition, there are also cell- and tissue-specific processes which are subject to NAD-mediated regulation. For example, insulin secretion is regulated by four different mechanisms of NAD-dependent signaling.

Unlike redox reactions, signaling causes permanent NAD degradation. Accordingly, NAD biosynthetic pathways, too, constitute a complex array of conversions with emerging regulatory roles and direct relationships to the signaling processes, besides feeding energetic needs. While the importance of NAD-dependent signaling pathways has been impressively demonstrated, even at the organismal level, some key issues still remain elusive. It is, for example, interesting to note that nuclear poly-ADP-ribosylation can promote apoptosis, while transcriptional silencing mediated by the human Sir2 homologue, SIRT1, facilitates life span extension. Evidence is accumulating that the availability of the substrate, NAD, may be a major limiting and therefore decisive regulatory factor. For example, modulation of the rate-limiting step in NAD biosynthesis causes shifts in the circadian rhythm and affects the capacity to counteract cellular stress. We have demonstrated that a nuclear enzyme of NAD biosynthesis directly supplies NAD to poly-ADP-ribose polymerase-1 (PARP1). Thereby, local NAD synthesis regulates DNA repair and PARP1-dependent apoptosis. A similar localized NAD generation in nerve ends has now been reported to be critical for axonal integrity, although the precise mechanism is still unknown. Thus, the subcellular distribution of NAD biosynthesis has emerged as a factor controlling cellular functions. Our recent work has focussed on the question as to how subcellular NAD pools are generated and possibly interact. We developed molecular tools that enabled identification of the mechanisms of mitochondrial NAD synthesis in human cells. Mitochondria contain the largest subcellular NAD pool, which is essential for both energy and signal transduction and has implications for a number of diseases.

Host: Jaakko Saraste , Department of Biomedicine