“Genetically-Encoded Sensors for Metabolic Pathways”

The Cambronne lab studies how metabolites are regulated in different parts of the cell to control signaling pathways and gene expression. We develop genetically-encoded fluorescent biosensors for localized and real-time measurements of these metabolites. Our initial work has focused on oxidized nicotinamide adenine dinucleotide (NAD+) for its dual roles in oxidoreductive reactions and as the substrate for NAD+-consuming signaling enzymes. A mitochondrial NAD+ sensor led to de-orphaning mitochondrial carrier SLC25A51 as the major transporter of free NAD+ in humans. We found that the selectivity of SLC25A51 for oxidized NAD⁺ can be attributed to charged interactions between the nicotinamide ring and an acidic patch in the central pore of SLC25A51. With its selectivity for oxidized NAD⁺, SLC25A51 serves as an uncoupler for NAD⁺/NADH ratios in mitochondria, and as such, a promising vulnerability in oxidative cancers such as drug-refractory acute myeloid leukemias.