BBB seminar: Mathias Ziegler

Mathias Ziegler
Department of Biomedicine, University of Bergen

Nicotinamide adenine dinucleotide (NAD) is a vital molecule in all organisms. It plays a major role in all cells as cofactor in metabolic redox reactions and as substrate for signal transduction, processes that undergo critical changes in a variety of diseases. NAD-dependent signalling pathways include poly- and mono-ADP-ribosylation, protein deacetylation by sirtuins and generation of messengers involved in Ca²⁺ signalling. They mediate fundamental events such as transcription, DNA repair, cell cycle progression and apoptosis. Moreover, they contribute to epigenetic regulation and the control of metabolism. All these signalling reactions include the degradation of NAD to nicotinamide. In fact, NAD turnover appears to be unexpectedly rapid in human cells suggesting that NAD-dependent signalling processes are highly active. Consequently, the high rate of NAD consumption necessitates robust NAD biosynthesis, in particular, efficient recycling of the vitamin precursor nicotinamide. Given this increasing awareness, the routes, molecular mechanisms and regulation of NAD biosynthesis have also become the subject of intense research. The commonly known precursors of NAD biosynthesis are nicotinic acid and nicotinamide (known as vitamin B3). However, their riboside derivatives now appear to be of similar importance. Impressive progress has been made regarding the molecular identification, functional and structural characterization as well as regulation of the human NAD biosynthetic and signalling enzymes. Both phylogenetic analyses and metabolic modelling approaches are increasingly contributing to the understanding of this complex metabolic and signalling network. Recent analyses have unravelled relationships between NAD biosynthetic and consuming processes pointing towards evolutionary advantages of diversifying signalling pathways concomitantly with the selection for highly efficient NAD biosynthesis and its compartmentalization. Kinetic modelling has supported this idea and suggested an unexpected optimization of kinetic properties to enable high NAD turnover.

Exciting therapeutic concepts have emerged, which aim at modulation of NAD availability or to target individual signalling pathways. Unfortunately, so far the set of selective drugs is rather limited. However, it appears that increasing NAD availability by supplementation with alternative vitamin derivatives bears great potential to counteract a variety of pathological conditions, in particular, age-associated diseases such as diabetes, neurodegeneration and cancer.

Chairperson: Frode Berven, Department of Biomedicine