Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-34850-0
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Funding
- Natural Science Foundation of China [81972567, 82030093]
- Beijing Municipal Institute of Public Medical Research Development and Reform Pilot Project, and Support Project for High-Level Teachers in Beijing Municipal Universities during the Period of 13th Five-Year Plan [Jingyiyan-2021-10, CITTCD20190333]
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This study reveals the pathophysiological role of deregulated purine biosynthesis in NADH accumulation-associated disorders and demonstrates the utility of manipulating NADH/NAD(+) and NADPH/NADP(+) using genetic tools. The authors develop a genetic tool to manipulate the ratios of cellular NADH/NAD(+) and NADPH/NADP(+), and identify purine biosynthesis as an NADH-sensing pathway to mediate reductive stress.
An enhanced NADH/NAD(+) ratio, termed reductive stress, is associated with many diseases. However, whether a downstream sensing pathway exists to mediate pathogenic outcomes remains unclear. Here, we generate a soluble pyridine nucleotide transhydrogenase from Escherichia coli (EcSTH), which can elevate the NADH/NAD(+) ratio and meantime reduce the NADPH/NADP(+) ratio. Additionally, we fuse EcSTH with previously described LbNOX (a water-forming NADH oxidase from Lactobacillus brevis) to resume the NADH/NAD(+) ratio. With these tools and by using genome-wide CRISPR/Cas9 library screens and metabolic profiling in mammalian cells, we find that accumulated NADH deregulates PRPS2 (Ribose-phosphate pyrophosphokinase 2)-mediated downstream purine biosynthesis to provoke massive energy consumption, and therefore, the induction of energy stress. Blocking purine biosynthesis prevents NADH accumulation-associated cell death in vitro and tissue injury in vivo. These results underscore the pathophysiological role of deregulated purine biosynthesis in NADH accumulation-associated disorders and demonstrate the utility of EcSTH in manipulating NADH/NAD(+) and NADPH/NADP(+). Reductive stress, reflected by the elevated intracellular NADH/NAD(+) ratio, is associated with multiple human diseases. Here, the authors develop a genetic tool to manipulate the ratios of cellular NADH/NAD(+) and NADPH/NADP(+), and identify purine biosynthesis as an NADH-sensing pathway to mediate reductive stress.
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