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

Author

Listed:
  • Ronghui Yang

    (Capital Medical University
    Capital Medical University)

  • Chuanzhen Yang

    (Capital Medical University
    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
    Capital Medical University)

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+.

Suggested Citation

  • Ronghui Yang & Chuanzhen Yang & Lingdi Ma & Yiliang Zhao & Zihao Guo & Jing Niu & Qiaoyun Chu & Yingmin Ma & Binghui Li, 2022. "Identification of purine biosynthesis as an NADH-sensing pathway to mediate energy stress," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34850-0
    DOI: 10.1038/s41467-022-34850-0
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    References listed on IDEAS

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    1. Russell P. Goodman & Andrew L. Markhard & Hardik Shah & Rohit Sharma & Owen S. Skinner & Clary B. Clish & Amy Deik & Anupam Patgiri & Yu-Han H. Hsu & Ricard Masia & Hye Lim Noh & Sujin Suk & Olga Gold, 2020. "Hepatic NADH reductive stress underlies common variation in metabolic traits," Nature, Nature, vol. 583(7814), pages 122-126, July.
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    Cited by:

    1. Zhao, Zisheng & Wu, Hongxin & An, Yu & Zhang, Yuhan & Huang, Fuxin & Wang, Kang & Zhang, Guangyi, 2024. "Insights into mechanisms of red mud promoting biogas production from waste activated sludge anaerobic digestion," Renewable Energy, Elsevier, vol. 232(C).

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