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

Authors

Qinghui Shang, Xuepeng Bian, Shujie Lou

Published in

Frontiers in cell and developmental biology. Volume 14. Pages 1929409. Epub Sep 29, 2026.

Abstract

Beyond its traditional role as a glycolysis end-product, lactate is now recognized as an important signaling molecule influencing synaptic plasticity and mitochondrial activity.
We examined whether lactate, acting through its receptor GPR81, improves synaptic plasticity-related protein expression by augmenting mitochondrial biogenesis and fusion.
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.
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.
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.

PMID:
42871135
Bibliographic data and abstract were imported from PubMed on 14 Oct 2026.

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