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

Yuki Kamijo, Philipp Mächler, Natalie Ness, Cong Quang Vu, Tsukasa Kusakizako, Jamsad Mannuthodikayil, Zaneta Ku, Marc Boisvert, Ekaterina Grebenik, Ikumi Miyazaki, Rina Hashizume, Haruaki Sato, Rui Liu, Yukiko Hori, Taisuke Tomita, Tetsuro Katayama, Akihiro Furube, Gabriela Caraveo, Marie-Eve Paquet, Mikhail Drobizhev, Osamu Nureki, Satoshi Arai, Marco Brancaccio, Robert E. Campbell, David Kleinfeld and Yusuke Nasu ()
Additional contact information
Yuki Kamijo: The University of Tokyo
Philipp Mächler: University of California San Diego
Natalie Ness: 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
Mikhail Drobizhev: Montana State University
Osamu Nureki: The University of Tokyo
Satoshi Arai: Kanazawa University
Marco Brancaccio: Imperial College London
Robert E. Campbell: The University of Tokyo
David Kleinfeld: University of California San Diego
Yusuke Nasu: The University of Tokyo

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64484-x

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