BBB seminar: Mathias Ziegler
Bioenergetics meets signalling: Unexpected regulatory functions of NAD(P)
Department of Molecular Biology, University of Bergen
Recent research has unravelled an unexpectedly wide array of signalling pathways involving nicotinamide adenine dinucleotide (NAD) and its phosphorylated form, NADP. NAD serves as substrate for protein modification including protein deacetylation, and mono- and poly-ADP-ribosylation. NAD and NADP are also precursors of intracellular calcium-mobilizing messenger molecules. It is now beyond doubt that NAD(P)-mediated signal transduction does not merely regulate metabolic pathways, but might hold a key position in the control of fundamental cellular processes including cell cycle regulation, DNA repair, transcription and apoptosis.
Our research focuses on the molecular identification, cell-biological characterization and physiological regulation of NAD(P) biosynthesis and signalling reactions. Particular attention is paid to the elucidation of compartment-specific roles of these pathways and their relevance to bioenergetics, genotoxic and oxidative stress and ensuing pathological states. For example, poly-ADP-ribosylation is primarily a nuclear process triggered by DNA damage. Depending on the extent of DNA damage this protein modification may use up almost the entire cellular NAD. Since most of the cellular NAD is located within mitochondria, there has to be a mechanism permitting access of nuclear enzymes to mitochondrial NAD. Interestingly, both the major consumer of NAD, poly-ADP-ribose polymerase 1 (PARP1), and a key enzyme of NAD synthesis, NMNAT1, are located within the nucleus. We recently demonstrated that NMNAT1 may activate the catalytic activity of PARP1 in vivo and in vitro. Thereby, synthesis and consumption of NAD are tightly linked which appears to be important for the regulation of key nuclear events.
For an overview see: Trends Biochem. Sci. (2004) 29, 111-118.