Understanding and Treating NAXD Deficiency Using Vitamin B3-Based Approaches - PROJECT SUMMARY The past decade has seen significant interest in vitamin B3 therapies for age-associated conditions and mitochondrial diseases, yet a systematic understanding of which disorders might benefit remains elusive. Here, we present a focused investigation into NAXD deficiency, identified through genome-wide CRISPR screens as a potential target for B3 therapy. Our research demonstrates that NAXD, a critical proofreading enzyme in the NAD+ metabolism pathway, plays a pivotal role in preventing cellular dysfunction. Through the development of a NAXD knockout mouse model, we aim to elucidate the organ-specific pathologies associated with NAXD deficiency, including neuropathology, cardiac dysfunction, and skin lesions. Additionally, we seek to understand the pathophysiology of NAXD disease, exploring both NADH depletion and the toxic effects of NADHX accumulation on oxidoreductase function. Furthermore, we investigate the potential of environmental and dietary interventions, including B3 megavitamin therapy and serine supplementation, in mitigating NAXD-associated phenotypes. Our study not only offers insights into NAXD deficiency but also serves as a template for systematically determining which diseases benefit from each vitamin.
