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Mitochondrial NADP(H) generation is essential for proline biosynthesis

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Science  28 May 2021:
Vol. 372, Issue 6545, pp. 968-972
DOI: 10.1126/science.abd5491

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  • RE: Mitochondrial NADP(H) generation is essential for various amino acid biosynthesis including proline
    • Bo Liu, post-doctoral, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
    • Other Contributors:
      • Shuang-Jiang Liu, professor, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
      • Yong Tao, professor, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China

    In their Research Article, “Mitochondrial NADP(H) generation is essential for proline biosynthesis” (Vol 372, Issue 6540, 23 April 2021, 1), J. Zhu et al. write that mitochondrial NADP(H) production depends on the phosphorylation of NAD(H) by NAD kinase 2 (NADK2), deletion of NADK2 in human cell lines led to impaired cell growth in minimal medium, and this growth defect was rescued by proline supplementation. Their argument assumes that NADK2-mediated mitochondrial NADP(H) generation was required for the reduction of glutamate and hence proline biosynthesis, and then cell growth. However, this conclusion may flaw considering that the minimal DMEM medium they used contained significant amounts of glutamine (2-5 mM).
    In mitochondrion, TCA cycle produce α-ketoglutarate and reducing power from glucose for the biosynthesis of glutamate (2), not only a precursor for proline biosynthesis, but a common amino donor for other essential amino-acid biosynthesis, such as alanine, aspartate, etc (3). In their experiment, glutamate was directly available from medium glutamine deamination, and the distribution of NADK2-mediated mitochondrial NADP(H) pool could not be evaluated accurately, on account of considerable NADP(H) was required in biosynthesis of glutamate through a NADPH-dependent glutamate dehydrogenase (2). Therefore, mitochondrial NADP(H) pool deserves a more comprehensive analysis and research.

    References and Notes
    1. Zhu, J., Schwörer, S., Berisa, M., Kyun...

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    Competing Interests: None declared.

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