Regulation of brain energy metabolism by NAD and sirtuins
All cells require a constant supply of energy to survive, however the active and dynamic environment within the brain imposes not only a high basal energy requirement, but also vastly fluctuating energy demands across the course of a normal day. The mechanisms that maintain the brain’s exquisite responsiveness to the marked variations in energy demands are currently unresolved. One emerging control mechanism in brain metabolism is the regulation of bioenergetic pathways by protein acetylation. Acetylation is a post-translational modification involving the addition of an acetyl group to amino acids such as lysine. Acetylation can have rapid effects on protein function by altering stability, enzymatic activity and sub-cellular localisation.
The key enzymes responsible for lysine de-acetylation, the silent information regulators or sirtuins SIRT1, 2 and 3, are crucial in the removal of acetate from enzymes. Sirtuins are dependent on nicotinamide adenine dinucleotide (NAD+) for this process, meaning that NAD+ availability also plays a major role in acetylation control. Sirtuins have been implicated in a wide range of protective and enhancing activities, including prevention of hypoxic, oxidative, metabolic and age-related damage. Discovery of the true abilities of this group of enzymes and their dependent factor NAD+ is really just beginning. In the brain, where bioenergetic dysfunction underlies a range of neurological diseases and normal aging, restoration of function via sirtuins and NAD+ arguably holds the greatest therapeutic potential.
This project is investigating control of metabolism by sirtuins and by NAD+ availability using an innovative, pharmacogenetic approach to metabolism research and “world-first” cell-specific introduction of enzymes into tissue in vivo. It will deliver an integrated picture of how SIRTs 1-3 and NAD+ interact with metabolism, crucial for development of next generation treatments based on this system. Finally, in preclinical translation, we will test the therapeutic effects of manipulating this system to combat decreased NAD+ availability and SIRT activity within the aging brain.