Key Findings
A research team at the Kavli Institute has engineered groundbreaking calcium-independent biosensors, designated ‘eLACCO3’ and ‘R-eLACCO3,’ enabling multiplexed in vivo imaging of extracellular L-lactate dynamics. These novel fluorescent cell-surface lactate biosensors are characterized by their stable Ca2+-independent responses and significantly faster response and recovery kinetics in cultured cells compared to conventional sensors. This marks a powerful advancement for deepening the understanding of complex metabolic dynamics in living systems.
Technical / Clinical Details
The developed biosensors, eLACCO3 and its red-shifted counterpart R-eLACCO3, are fluorescent probes specifically designed to detect extracellular L-lactate. Their most critical technical feature is their calcium independence. Many existing fluorescent biosensors are susceptible to intracellular calcium fluctuations, making it challenging to precisely isolate and measure the dynamics of specific metabolites like lactate. eLACCO3 overcomes this limitation, reliably reporting lactate concentrations regardless of changes in cellular physiological states. Furthermore, evaluations in cultured cells have demonstrated that these sensors exhibit extremely rapid response and recovery times, enabling real-time capture of transient and rapid fluctuations in lactate levels. The availability of both green and red biosensors facilitates ‘multiplex imaging,’ allowing simultaneous monitoring of lactate dynamics in different cell types or brain regions. This is particularly useful for studying intercellular interactions, such as the coupling between glucose and lactate metabolism, or metabolite transport between neurons and glial cells. The capability for multiplexed in vivo measurements opens new windows for a more comprehensive understanding of lactate’s role in brain activity, energy metabolism, and disease progression.
Background & Context
Lactate, once considered merely a metabolic waste product, has recently been recognized for its crucial roles as an intercellular signaling molecule, an energy substrate, and a modulator of neuronal activity. Particularly in the brain, the ‘astrocyte-neuron lactate shuttle’ hypothesis posits that lactate produced by glial cells during neuronal hyperexcitation is supplied to neurons, suggesting its involvement in memory formation, learning, and the pathophysiology of neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s) and stroke. However, technologies for real-time, high-resolution tracking of extracellular lactate dynamics in vivo have been limited. The development of these biosensors is expected to bridge this research gap and yield new insights into the role of lactate.
Strategic Significance & Outlook
The eLACCO3 and R-eLACCO3 biosensors are poised to significantly impact a wide range of research fields where lactate plays a crucial role, including neuroscience, cancer research, and exercise physiology. Specifically, the highly precise in vivo imaging of lactate dynamics in brain slices, cultured cells, and ultimately live animal models is expected to contribute to elucidating disease mechanisms and identifying novel therapeutic targets. In the future, these sensor technologies may also be considered for integration into more advanced genetically encoded biosensors or wearable devices, extending their application from basic research to clinical diagnostics.
Source: https://preprints.kavlimeetings.org/2026/10/05/all/neuro/ucsd-salk/265018/
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