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Lysosomes couple nutrient status to cellular energetics through the mechanistic target of rapamycin complex 1 (mTORC1) and the autophagy\u2013lysosome pathway, yet their \u00adsubcellular contribution to neuronal metabolic profiles remains unclear. To address this, we established an in vivo AAV-LysoTag\/Lyso-IP workflow combined with metabolomics to quantify metabolites within mouse hippocampal lysosomes. An in vitro Lyso-IP platform and immunofluorescence provided cell-based validation. Under every-other-day fasting, hippocampal lysosomes exhibited reprogramming: small-molecule substrates derived from amino acids and fatty acids accumulated; bis(monoacylglycero)phosphate was upregulated, indicating enhanced intraluminal vesicle formation and lipid degradation\/sorting; \u00adsphingolipids and cardiolipin increased, consistent with selective mitophagy. Notably, high basal lysosomal levels of malic acid and \u03b1-ketoglutarate (\u03b1-KG) suggested additional sources beyond the mitochondria. Immunofluorescence further showed lysosomal localization of isocitrate dehydrogenase and fumarate hydratase, suggesting partial residency of these enzymes. The oxoglutarate carrier (SLC25A11) signals were observed in LAMP1+ compartments, suggesting potential transmembrane exchange of \u03b1-KG and malic acid. Together, our data indicate that lysosomal tricarboxylic acid -related metabolites are maintained by three parallel routes: mitochondrial delivery to lysosomes, local production by resident enzymes, and transporter-mediated exchange. These metabolites supplement and reshape neuronal carbon flux and metabolic resilience at the subcellular level. Our findings elevate lysosomes from degradative endpoints to mobilizable metabolic hubs in the brain and provide both methodological and conceptual frameworks for neurometabolic adaptation under energy scarcity.<\/jats:p>","DOI":"10.1093\/lifemeta\/loag005","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T12:31:14Z","timestamp":1771331474000},"source":"Crossref","is-referenced-by-count":1,"title":["Lysosomes contribute to the synthesis of tricarboxylic acid-related metabolites in the hippocampus"],"prefix":"10.1093","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2053-5358","authenticated-orcid":false,"given":"Liangliang","family":"Kong","sequence":"first","affiliation":[{"name":"Department of Pharmacology, State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Fudan University , Shanghai 200032,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongying","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Fudan University , Shanghai 200032,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoting","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Fudan University , Shanghai 200032,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqing","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Fudan University , Shanghai 200032,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Fudan University , Shanghai 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