Recently, glycerol-3-phosphate dehydrogenase 1-like (GPD1-L) gene mutations have been shown to reduce cardiac Na + current and cause Brugada Syndrome (BrS). The glycerol-3-phosphate dehydrogenase (GPD) family of genes is involved in nicotinamide adenine dinucleotides (NAD)-dependent energy metabolism, and GDP1-L has >80% amino acid homology with GPD. Therefore, we tested whether mutations in GPD1-L could be acting through NAD (H) to alter Na + current. Human embryonic kidney (HEK) cells stably expressing the human cardiac sodium channel (SCN5A) were used to assess the effects of wild-type (WT) and mutant (MT) GPD1-L on cellular NAD(H) and the effects of NAD(H) on Na + current. A mouse model of BrS was used to assess the effect of reduced NAD + on arrhythmic risk. MT GPD1-L raised cellular NADH level by 4.3 fold (p<0.01) and reduced Na + current by 69.9% (p<0.01). Extracellular NADH (300 μM) raised cellular NADH by 5.3 fold and decreased whole cell peak conductance by 71.4% (p<0.001). Extracellular NAD + (300 μM) raised conductance by 30.3% (p< 0.001). Fluorescent microscopy showed parallel changes in membrane-associated, GFP-tagged Na + channels. Intracellular application of NADH or NAD + resulted in an immediate change in Na + current of −55.5% (p < 0.01) and +66.6% (p < 0.01), respectively. External NAD + could prevent the reduction in Na + current caused by MT GPD1-L. Apocynin (100 μM), an NAD(P)H oxidase inhibitor, or the reducing agent, dithiothreitol (DTT), prevented the NADH-induced reduction in Na + current (p < 0.01). Application of 100 μM NAD + to a mouse model of BrS reduced the programmed electrical stimulation induced ventricular tachycardia. GPD1-L mutations may cause BrS through alterations in cellular NAD(H), and NAD + might represent a novel treatment for BrS.