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Functions, Mechanisms, and therapeutic applications of the inositol pyrophosphates 5PP-InsP5 and InsP8 in mammalian cells

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Abstract

Water-soluble myo-inositol phosphates have long been characterized as second messengers. The signaling properties of these compounds are determined by the number and arrangement of phosphate groups on the myo-inositol backbone. Recently, higher inositol phosphates with pyrophosphate groups were recognized as signaling molecules. 5-Diphosphoinositol 1,2,3,4,6-pentakisphosphate (5PP-InsP5) is the most abundant isoform, constituting more than 90% of intracellular inositol pyrophosphates. 5PP-InsP5 can be further phosphorylated to 1,5-bisdiphosphoinositol 2,3,4,6-tetrakisphosphate (InsP8). These two molecules, 5PP-InsP5 and InsP8, are present in various subcellular compartments, where they participate in regulating diverse cellular processes such as cell death, energy homeostasis, and cytoskeletal dynamics. The synthesis and metabolism of inositol pyrophosphates are subjected to tight regulation, allowing for their highly specific functions. Blocking the 5PP-InsP5/InsP8 signaling pathway by inhibiting the biosynthesis of 5PP-InsP5 demonstrates therapeutic benefits in preclinical studies, and thus holds promise as a therapeutic approach for certain diseases treatment, such as metabolic disorders.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82220108021, 82070259) and the Natural Science Foundation of Shanghai (22ZR1440700). We thank the thoughtful input from Dr. Dorothea Fiedler. We also thank Alfred C. Chin for editing this manuscript.

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Authors and Affiliations

  1. Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China

    Ji Qi, Yuanyuan Chen, Alex F. Chen & Chenglai Fu

  2. Department of Critical Care Unit, Ningbo Medical Center Li Huili Hospital, Ningbo University, Ningbo, 315040, Zhejiang, China

    Linhui Shi

  3. Department of Trauma Orthopedics, Ningbo No.6 Hospital, Ningbo, 315040, China

    Limei Zhu

  4. Department of Obstetrics and Gynecology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China

    Hong Zhu

  5. Department of Nuclear Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China

    Weiwei Cheng

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A.F.C. and C.F. conceptualized. C.F. wrote the manuscript. J.Q. drew the diagrams and completed the tables. J.Q., L.S., L.Z., Y.C., H.Z., and W.C. revised and edited the manuscript.

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Qi, J., Shi, L., Zhu, L. et al. Functions, Mechanisms, and therapeutic applications of the inositol pyrophosphates 5PP-InsP5 and InsP8 in mammalian cells. J. of Cardiovasc. Trans. Res. 17, 197–215 (2024). https://doi.org/10.1007/s12265-023-10427-0

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