{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:05:15Z","timestamp":1790661915711,"version":"4.1.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Beyond its traditional role as a glycolysis end-product, lactate is now recognized as an important signaling molecule influencing synaptic plasticity and mitochondrial activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>We examined whether lactate, acting through its receptor GPR81, improves synaptic plasticity-related protein expression by augmenting mitochondrial biogenesis and fusion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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-1\u03b1, NRF1\/2, TFAM), fusion (OPA1, MFN2), and synaptic plasticity (BDNF, PSD95, SYN). In Neuro-2A cells, pathways were blocked using the PGC-1\u03b1 inhibitor SR-18292 or the fusion inhibitor MF18 after lactate\/GPR81 activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>L-lactate and 3OBA significantly enhance mitochondrial function, including increasing ATP production, upregulating key regulators of mitochondrial biogenesis (PGC-1\u03b1, 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-1\u03b1 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1929409","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:46:59Z","timestamp":1790660819000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Lactate promotes mitochondrial biogenesis and fusion via GPR81 to enhance synaptic plasticity-related protein expression in hippocampal cells"],"prefix":"10.3389","volume":"14","author":[{"given":"Qinghui","family":"Shang","sequence":"first","affiliation":[{"name":"College of Sports and Health, Shandong Sport University","place":["Jinan, China"]},{"name":"School of Exercise and Health Sciences, Shanghai University of Sport","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuepeng","family":"Bian","sequence":"additional","affiliation":[{"name":"School of Exercise and Health Sciences, Shanghai University of Sport","place":["Shanghai, China"]},{"name":"Department of Rehabilitation, School of International Medical Technology, Shanghai Sanda University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujie","family":"Lou","sequence":"additional","affiliation":[{"name":"School of Exercise and Health Sciences, Shanghai University of Sport","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1117146","DOI":"10.3389\/fnmol.2023.1117146","article-title":"Exogenous L-lactate administration in rat hippocampus increases expression of key regulators of mitochondrial biogenesis and antioxidant defense","volume":"16","author":"Akter","year":"","journal-title":"Front. 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