Lactate promotes mitochondrial biogenesis and fusion via GPR81 to enhance synaptic plasticity-related protein expression in hippocampal cells.

Background: Beyond its traditional role as a glycolysis end-product, lactate is now recognized as an important signaling molecule influencing synaptic plasticity and mitochondrial activity. Objective: We examined whether lactate, acting through its receptor GPR81, improves synaptic plasticity-related protein expression by augmenting mitochondrial biogenesis and fusion. Methods: Primary hippocampal cells and Neuro-2A cells were studied. Hippocampal cells received L-lactate or the GPR81 agonist 3OBA. We measured ATP production and levels of proteins involved in mitochondrial biogenesis (PGC-1α, NRF1/2, TFAM), fusion (OPA1, MFN2), and synaptic plasticity (BDNF, PSD95, SYN). In Neuro-2A cells, pathways were blocked using the PGC-1α inhibitor SR-18292 or the fusion inhibitor MF18 after lactate/GPR81 activation. Results: L-lactate and 3OBA significantly enhance mitochondrial function, including increasing ATP production, upregulating key regulators of mitochondrial biogenesis (PGC-1α, NRF1/2, and TFAM), and promoting fusion proteins (OPA1 and MFN2) that maintain mitochondrial network integrity. These mitochondrial improvements were paralleled by elevated expression of synaptic plasticity-related protein expression (BDNF, PSD95, and SYN), suggesting functional coupling between metabolic and synaptic processes. Conversely, pharmacological inhibition of mitochondrial biogenesis (via PGC-1α inhibitor SR-18292) or fusion (using MF18) abolished lactate/GPR81-mediated benefits, resulting in reduced ATP levels, impaired mitochondrial membrane potential, and downregulation of synaptic proteins. Conclusion: Our findings reveal that lactate promotes mitochondrial biogenesis and fusion via GPR81 to enhance synaptic plasticity-related protein expression in hippocampal cells, highlighting a novel mechanism by which lactate supports neuronal energy demands and synaptic plasticity.