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A red fluorescent genetically encoded biosensor for in vivo imaging of extracellular l-lactate dynamics

Author

Listed:
  • Yuki Kamijo

    (The University of Tokyo)

  • Philipp Mächler

    (University of California San Diego)

  • Natalie Ness

    (Imperial College London
    UK Dementia Research Institute at Imperial College London)

  • Cong Quang Vu

    (Kanazawa University)

  • Tsukasa Kusakizako

    (The University of Tokyo)

  • Jamsad Mannuthodikayil

    (Academia Sinica)

  • Zaneta Ku

    (University of California San Diego)

  • Marc Boisvert

    (Laval University)

  • Ekaterina Grebenik

    (Northwestern University Feinberg School of Medicine)

  • Ikumi Miyazaki

    (The University of Tokyo)

  • Rina Hashizume

    (The University of Tokyo)

  • Haruaki Sato

    (The University of Tokyo)

  • Rui Liu

    (University of California San Diego)

  • Yukiko Hori

    (The University of Tokyo)

  • Taisuke Tomita

    (The University of Tokyo)

  • Tetsuro Katayama

    (Tokushima University)

  • Akihiro Furube

    (Tokushima University)

  • Gabriela Caraveo

    (Northwestern University Feinberg School of Medicine)

  • Marie-Eve Paquet

    (Laval University
    Laval University)

  • Mikhail Drobizhev

    (Montana State University)

  • Osamu Nureki

    (The University of Tokyo)

  • Satoshi Arai

    (Kanazawa University)

  • Marco Brancaccio

    (Imperial College London
    UK Dementia Research Institute at Imperial College London)

  • Robert E. Campbell

    (The University of Tokyo
    Laval University
    Laval University)

  • David Kleinfeld

    (University of California San Diego
    University of California San Diego)

  • Yusuke Nasu

    (The University of Tokyo
    Academia Sinica
    National Taiwan University)

Abstract

l-Lactate is increasingly recognized as an intercellular energy currency in mammals, but mysteries remain regarding the spatial and temporal dynamics of its release and uptake between cells via the extracellular environment. Here we introduce R-eLACCO2.1, a red fluorescent extracellular l-lactate biosensor that is superior to previously reported green fluorescent biosensors in in vivo sensitivity to increases in extracellular l-lactate and spectral orthogonality. R-eLACCO2.1 exhibits excellent fluorescence response in cultured cells, mouse brain slices, and live mice. R-eLACCO2.1 also serves as an effective fluorescence lifetime-based biosensor. Using R-eLACCO2.1, we monitor whisker stimulation and locomotion-induced changes in endogenous extracellular l-lactate in the somatosensory cortex of awake mice. To highlight the potential insights gained from in vivo measurements with R-eLACCO2.1, we perform dual-color imaging from the somatosensory cortex of actively locomoting mice. This enables us to simultaneously observe the neural activity, reported by a green fluorescent GCaMP calcium ion biosensor, and extracellular l-lactate. As the high-performance tool in the suite of extracellular l-lactate biosensors, R-eLACCO2.1 is ideally suited to delimit the emerging roles of l-lactate in mammalian metabolism.

Suggested Citation

  • Yuki Kamijo & Philipp Mächler & Natalie Ness & Cong Quang Vu & Tsukasa Kusakizako & Jamsad Mannuthodikayil & Zaneta Ku & Marc Boisvert & Ekaterina Grebenik & Ikumi Miyazaki & Rina Hashizume & Haruaki , 2025. "A red fluorescent genetically encoded biosensor for in vivo imaging of extracellular l-lactate dynamics," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64484-x
    DOI: 10.1038/s41467-025-64484-x
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    References listed on IDEAS

    as
    1. Daniel Jimenez-Blasco & Arnau Busquets-Garcia & Etienne Hebert-Chatelain & Roman Serrat & Carlos Vicente-Gutierrez & Christina Ioannidou & Paula Gómez-Sotres & Irene Lopez-Fabuel & Monica Resch-Beushe, 2020. "Glucose metabolism links astroglial mitochondria to cannabinoid effects," Nature, Nature, vol. 583(7817), pages 603-608, July.
    2. Yusuke Nasu & Abhi Aggarwal & Giang N. T. Le & Camilla Trang Vo & Yuki Kambe & Xinxing Wang & Felix R. M. Beinlich & Ashley Bomin Lee & Tina R. Ram & Fangying Wang & Kelsea A. Gorzo & Yuki Kamijo & Ma, 2023. "Lactate biosensors for spectrally and spatially multiplexed fluorescence imaging," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
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