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Most nephrotoxins damage the proximal tubule (PT), causing functional impairment of solute reabsorption and systemic metabolic complications. The antiviral drug tenofovir disoproxil fumarate (TDF) is an archetypal nephrotoxin, inducing mitochondrial abnormalities and urinary solute wasting, for reasons that were previously unclear. Here, we developed an automated, high-throughput imaging pipeline to screen the effects of TDF on solute transport and mitochondrial morphology in human-derived RPTEC\/TERT1 cells, and leveraged this to generate realistic models of functional toxicity. By applying multiparametric metabolic profiling\u2014including oxygen consumption measurements, metabolomics, and transcriptomics\u2014we elucidated a highly robust molecular fingerprint of TDF exposure. Crucially, we identified that the active metabolite inhibits complex V (ATP synthase), and that TDF treatment causes rapid, dose-dependent loss of complex V activity and expression. Moreover, we found evidence of complex V suppression in kidney biopsies from humans with TDF toxicity. Thus, we demonstrate an effective and convenient experimental approach to screen for disease relevant functional defects in kidney cells in vitro, and reveal a new paradigm for understanding the pathogenesis of a substantial cause of nephrotoxicity.<\/jats:p>","DOI":"10.1093\/function\/zqac065","type":"journal-article","created":{"date-parts":[[2022,12,24]],"date-time":"2022-12-24T18:51:25Z","timestamp":1671907885000},"source":"Crossref","is-referenced-by-count":10,"title":["Integration of High-Throughput Imaging and Multiparametric Metabolic Profiling Reveals a Mitochondrial Mechanism of Tenofovir Toxicity"],"prefix":"10.1152","volume":"4","author":[{"given":"Adam","family":"Pearson","sequence":"first","affiliation":[{"name":"Institute of Anatomy, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Haenni","sequence":"additional","affiliation":[{"name":"Center for Microscopy and Image Analysis, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamal","family":"Bouitbir","sequence":"additional","affiliation":[{"name":"Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel , Klingelbergstrasse 50, CH-4056 Basel , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Hunt","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Newcastle University, Framlington Place, Newcastle upon Tyne , NE2 4HH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan A I","family":"Payne","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Newcastle University, Framlington Place, Newcastle upon Tyne , NE2 4HH , UK"},{"name":"Department of Infection and Tropical Medicine, Royal Victoria Infirmary , Queen Victoria Road, Newcastle upon Tyne NE1 4LP , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashwin","family":"Sachdeva","sequence":"additional","affiliation":[{"name":"Genito-Urinary Cancer Research Group, Division of Cancer Sciences, University of Manchester , Manchester, M20 4GJ, UK"},{"name":"Department of Surgery, The Christie Hospital NHS Foundation Trust , 550 Wilmslow Road, Manchester M20 4BX , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel K Y","family":"Hung","sequence":"additional","affiliation":[{"name":"King\u2019s College Hospital and School of Immunology & Microbial Sciences, King\u2019s College London , London, SE5 8AF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank A","family":"Post","sequence":"additional","affiliation":[{"name":"King\u2019s College Hospital and School of Immunology & Microbial Sciences, King\u2019s College London , London, SE5 8AF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Connolly","sequence":"additional","affiliation":[{"name":"UCL Centre for Nephrology, Royal Free Hospital , Rowland Hill Street, London NW3 2PF , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stellor","family":"Nlandu-Khodo","sequence":"additional","affiliation":[{"name":"Institute of Physiology, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nevena","family":"Jankovic","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milica","family":"Bugarski","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6328-7892","authenticated-orcid":false,"given":"Andrew M","family":"Hall","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich , Switzerland"},{"name":"Department of Nephrology, University Hospital Zurich , R\u00e4mistrasse 100, CH-8006 Zurich , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","published-online":{"date-parts":[[2022,12,24]]},"reference":[{"issue":"12","key":"2023011416261123300_bib1","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.2215\/CJN.00150118","article-title":"Pharmacology behind common drug nephrotoxicities","volume":"13","author":"Perazella","year":"2018","journal-title":"Clin J Am Soc 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