What do we study?
Our lab seeks to understand how metabolism superimposes its regulation on cellular processes.
We’re currently focused on the regulation of a key intermediary metabolite, nicotinamide adenine dinucleotide or NAD+.
Why do we care about NAD+?
This dinucleotide is synonymous with life, as there is no sustainable production of ATP without NAD+. Further, it has roles in post-translational modifications as the substrate and adduct used by Parp and Sirtuin enzymes, as well as in 2nd messenger signaling as the precursor for ADP-Ribose and cyclic-ADP-Ribose.
What is the problem?
Metabolic pathways are highly compartmentalized within tissue and even within a single cell. The challenge is matching the in situ method of study with the biological compartmentalization.
Our group develops and employs genetically encoded fluorescent sensors to measure free NAD+ in different parts of cells. These sensors have high spatial and temporal resolution and are used to take measurements in physiological contexts, both in real-time and non-invasively.
Most recently, our work with the mitochondrial sensor led to insight into how human mitochondria replenish their NAD+ levels and harness cellular energy (read about it here). This critical pool of NAD+ is typically the last to be depleted at the expense of cytoplasmic or nuclear pools when a cell is faced with stress.
What is the benefit?
Because maintenance of mitochondrial NAD+ is important for cell heath, how NAD+ gets into mitochondria is likely important in pathogenesis. We’re excited because this new regulatory point we’ve identified could represent a new disease etiology and also holds potential as a target for intervention.