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Defunctionalizing intracellular organelles such as mitochondria and peroxisomes with engineered phospholipase A/acyltransferases

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  • Satoshi Watanabe

    (Johns Hopkins University School of Medicine, Department of Cell Biology
    Johns Hopkins University School of Medicine, Center for Cell Dynamics
    Osaka University)

  • Yuta Nihongaki

    (Johns Hopkins University School of Medicine, Department of Cell Biology
    Johns Hopkins University School of Medicine, Center for Cell Dynamics)

  • Kie Itoh

    (Johns Hopkins University School of Medicine, Department of Cell Biology
    Johns Hopkins University School of Medicine, Center for Cell Dynamics
    Johns Hopkins University School of Medicine, Department of Neuroscience)

  • Toru Uyama

    (Kagawa University School of Medicine)

  • Satoshi Toda

    (Kanazawa University)

  • Shigeki Watanabe

    (Johns Hopkins University School of Medicine, Department of Cell Biology
    Johns Hopkins University School of Medicine, Center for Cell Dynamics
    Johns Hopkins University School of Medicine, Department of Neuroscience)

  • Takanari Inoue

    (Johns Hopkins University School of Medicine, Department of Cell Biology
    Johns Hopkins University School of Medicine, Center for Cell Dynamics)

Abstract

Organelles vitally achieve multifaceted functions to maintain cellular homeostasis. Genetic and pharmacological approaches to manipulate individual organelles are powerful in probing their physiological roles. However, many of them are either slow in action, limited to certain organelles, or rely on toxic agents. Here, we design a generalizable molecular tool utilizing phospholipase A/acyltransferases (PLAATs) for rapid defunctionalization of organelles via remodeling of the membrane phospholipids. In particular, we identify catalytically active PLAAT truncates with minimal unfavorable characteristics. Chemically-induced translocation of the optimized PLAAT to the mitochondria surface results in their rapid deformation in a phospholipase activity dependent manner, followed by loss of luminal proteins as well as dissipated membrane potential, thus invalidating the functionality. To demonstrate wide applicability, we then adapt the molecular tool in peroxisomes, and observe leakage of matrix-resident functional proteins. The technique is compatible with optogenetic control, viral delivery and operation in primary neuronal cultures. Due to such versatility, the PLAAT strategy should prove useful in studying organelle biology of diverse contexts.

Suggested Citation

  • Satoshi Watanabe & Yuta Nihongaki & Kie Itoh & Toru Uyama & Satoshi Toda & Shigeki Watanabe & Takanari Inoue, 2022. "Defunctionalizing intracellular organelles such as mitochondria and peroxisomes with engineered phospholipase A/acyltransferases," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31946-5
    DOI: 10.1038/s41467-022-31946-5
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    References listed on IDEAS

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    1. Hideaki Morishita & Tomoya Eguchi & Satoshi Tsukamoto & Yuriko Sakamaki & Satoru Takahashi & Chieko Saito & Ikuko Koyama-Honda & Noboru Mizushima, 2021. "Organelle degradation in the lens by PLAAT phospholipases," Nature, Nature, vol. 592(7855), pages 634-638, April.
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