{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T04:53:59Z","timestamp":1791089639890,"version":"4.1.0"},"reference-count":128,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DFG TRR353"],"award-info":[{"award-number":["DFG TRR353"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"award":["DFG TRR353"],"award-info":[{"award-number":["DFG TRR353"]}],"id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"publisher"}]},{"name":"European Union","award":["964537"],"award-info":[{"award-number":["964537"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"crossref"}]},{"name":"European Union","award":["101057014"],"award-info":[{"award-number":["101057014"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"crossref"}]},{"award":["964537"],"award-info":[{"award-number":["964537"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]},{"award":["101057014"],"award-info":[{"award-number":["101057014"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Redox stress and subsequent metabolic reprogramming are well-known consequences of neuronal exposure to mitochondrial toxicants. Here, we investigated, using human neuronal cultures, how such changes are quantitatively reflected in the patterns of cellular and extracellular amino acids. We asked whether these alterations may yield a mechanistically anchored biomarker for the type of neurotoxicity resulting from the impairment of the respiratory chain. Using a targeted metabolomics approach, we quantified intra- and extracellular amino acid pools and their temporal dynamics. Data were obtained from differentiated LUHMES neurons exposed to the complex I inhibitors berberine, 1-methyl-4-phenylpyridinium (MPP+), and tebufenpyrad, as well as to the non-mitochondrial toxicants MG-132 (proteasome inhibitor), RSL3 (glutathione peroxidase 4 inhibitor), and aerugine (fungal oxidative toxicant). The reductive stress, caused by mitochondrial inhibitors, was reflected in a characteristic and specific re-routing of amino acid metabolism, including increased Asn\/Asp and Gln\/Glu ratios and an upregulation of the electron acceptor Pro in neurons. Most conspicuous were the pronounced and reproducible increases in the lysine catabolites saccharopine (sacc) and \u03b1-aminoadipic acid (\u03b1-AAA). These two potential biomarkers of neuronal mitotoxicity were not altered by other types of toxicants. Moreover, the extent of concentration changes in sacc and \u03b1-AAA roughly correlated with the damaging effects of mitotoxicants, when assay conditions were (exposure period and exposure concentration). Our data provide an exemplary reference map of absolute amino acid concentrations in human cells and their culture medium. Moreover, sacch and \u03b1-AAA emerge as candidate biomarkers for neuroactive mitotoxicants and potentially for pathologies associated with impaired neuronal mitochondrial function.<\/jats:p>","DOI":"10.3390\/cells15191804","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:14:56Z","timestamp":1790936096000},"page":"1804","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Saccharopine and \u03b1-Aminoadipic Acid as Potential Biomarkers for Mitochondrial Stress in Neurons"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8696-7130","authenticated-orcid":false,"given":"Anna-Katharina","family":"\u00dcckert","sequence":"first","affiliation":[{"name":"In Vitro Toxicology and Biomedicine, Department Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457 Konstanz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Land","sequence":"additional","affiliation":[{"name":"In Vitro Toxicology and Biomedicine, Department Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457 Konstanz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina","family":"Pape","sequence":"additional","affiliation":[{"name":"In Vitro Toxicology and Biomedicine, Department Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457 Konstanz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahshid","family":"Alimohammadi","sequence":"additional","affiliation":[{"name":"In Vitro Toxicology and Biomedicine, Department Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457 Konstanz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivano","family":"Amelio","sequence":"additional","affiliation":[{"name":"Systems Toxicology, University of Konstanz, 78457 Konstanz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3778-8693","authenticated-orcid":false,"given":"Marcel","family":"Leist","sequence":"additional","affiliation":[{"name":"In Vitro Toxicology and Biomedicine, Department Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457 Konstanz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1002\/jat.2874","article-title":"Review: Toxicometabolomics","volume":"33","author":"Bouhifd","year":"2013","journal-title":"J. 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