Shedding light on in vivo metabolism: genetically encoded fluorescent biosensors for L-lactate
Traditionally regarded as a metabolic waste product of glycolysis, L-lactate (lactic acid) is now recognized as a key metabolite that functions both as an energy substrate and a signaling molecule. One prominent and debated model, the astrocyte-to-neuron lactate shuttle (ANLS) hypothesis, proposes that astrocyte-derived L-lactate is exported into the extracellular space and subsequently imported into neurons, where it is metabolized to support adenosine triphosphate (ATP) production during periods of elevated neuronal activity.
While genetically encoded calcium biosensors (e.g. GCaMP) have revolutionized our ability to monitor neuronal activity in vivo, tools for real-time imaging of key metabolites like L-lactate have lagged behind, limiting our ability to simultaneously interrogate neuronal activity and metabolism. This technical gap has hindered direct experimental validation of hypotheses such as ANLS.
In this seminar, we showcase the LACCO biosensor series, a family of genetically encoded fluorescent L-lactate biosensors engineered through directed protein evolution. These biosensors exhibit high sensitivity, specificity, and brightness, enabling dynamic visualization of L-lactate with subcellular resolution in living cells and in vivo. Using the LACCO biosensors and GCaMP biosensor, we demonstrated the concurrent imaging of neuronal activity and metabolism in awake mice. These results provide new avenues for dissecting metabolic coupling in the brain and represent a major technological advancement toward resolving long-standing debates such as the ANLS hypothesis.
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