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This study aimed to optimize the PeriTox assay, which uses peripheral neurons (PNs) and predicts the potential of chemicals to trigger peripheral neuropathies. By introducing a glucose-to-galactose switch in the medium composition, cells were forced to rely on mitochondrial respiration. Using pre-differentiated PNs cultured in either glucose (Glc) or galactose (Gal), we observed no major differences in baseline phenotype, gene expression, neurite outgrowth, or total ATP content. However, a marked metabolic shift was confirmed by the increased oxygen consumption in Gal conditions. Based on measurements of neurite growth and ATP levels, Gal-adapted neurons showed a heightened sensitivity, up to 7500-fold, to a range of mitochondrial respiratory chain (MRC) inhibitors. The sensitivity shift was high for inhibitors of MRC complexes I and III and modest or absent for unrelated compounds such as proteasome inhibitors or cytoskeletal poisons. For complex I-III inhibitors, the enhanced detection of mitochondrial neurotoxicants was coupled with a more accurate distinction between cytotoxic and neurite-specific effects, i.e., an improved assay specificity. In conclusion, our study on 39 compounds suggests that running the PeriTox assay in galactose increases its sensitivity and specificity for several mitochondrial toxicants, while no general disadvantages or shortcomings were observed. The modified version (PeriTox-M) may increase the performance of in vitro test batteries for scientific and regulatory applications.<\/jats:p>","DOI":"10.3390\/cells14231929","type":"journal-article","created":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T15:14:06Z","timestamp":1764861246000},"page":"1929","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["PeriTox-M, a Cell-Based Assay for Peripheral Neurotoxicity with Improved Sensitivity to Mitochondrial Inhibitors"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1453-1019","authenticated-orcid":false,"given":"Anna-Katharina","family":"Holzer","sequence":"first","affiliation":[{"name":"In Vitro Toxicology and Biomedicine, Department Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457 Konstanz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mira","family":"D\u00fcrr","sequence":"additional","affiliation":[{"name":"In Vitro Toxicology and Biomedicine, Department Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457 Konstanz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Selina","family":"Multrus","sequence":"additional","affiliation":[{"name":"In Vitro Toxicology and Biomedicine, Department Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457 Konstanz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Dangel","sequence":"additional","affiliation":[{"name":"In Vitro Toxicology and Biomedicine, Department Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457 Konstanz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Viktoria","family":"Magel","sequence":"additional","affiliation":[{"name":"In Vitro Toxicology and Biomedicine, Department Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457 Konstanz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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"},{"name":"Center for Alternatives to Animal Testing in Europe (CAAT-Europe), University of Konstanz, 78457 Konstanz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1007\/s00204-019-02473-y","article-title":"Development of a neurotoxicity assay that is tuned to detect mitochondrial toxicants","volume":"93","author":"Delp","year":"2019","journal-title":"Arch. 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