Identification of purine biosynthesis as an NADH-sensing pathway to mediate energy stress

Ronghui Yang, Chuanzhen Yang, Lingdi Ma, Yiliang Zhao, Zihao Guo, Jing Niu, Qiaoyun Chu, Yingmin Ma and Binghui Li ()
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Ronghui Yang: Capital Medical University
Chuanzhen Yang: Capital Medical University
Lingdi Ma: Capital Medical University
Yiliang Zhao: Capital Medical University
Zihao Guo: Capital Medical University
Jing Niu: Capital Medical University
Qiaoyun Chu: Capital Medical University
Yingmin Ma: Capital Medical University
Binghui Li: Capital Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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+.

Date: 2022
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DOI: 10.1038/s41467-022-34850-0

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