{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T05:03:11Z","timestamp":1784005391677,"version":"3.55.0"},"reference-count":112,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T00:00:00Z","timestamp":1714348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Forschungskommission of the Heinrich-Heine-University\/Duesseldorf"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The antipsychotic drug clozapine demonstrates superior efficacy in treatment-resistant schizophrenia, but its intracellular mode of action is not completely understood. Here, we analysed the effects of clozapine (2.5\u201320 \u00b5M) on metabolic fluxes, cell respiration, and intracellular ATP in human HL60 cells. Some results were confirmed in leukocytes of clozapine-treated patients. Neuroreceptor inhibition under clozapine reduced Akt activation with decreased glucose uptake, thereby inducing ER stress and the unfolded protein response (UPR). Metabolic profiling by liquid-chromatography\/mass-spectrometry revealed downregulation of glycolysis and the pentose phosphate pathway, thereby saving glucose to keep the electron transport chain working. Mitochondrial respiration was dampened by upregulation of the F0F1-ATPase inhibitory factor 1 (IF1) leading to 30\u201340% lower oxygen consumption in HL60 cells. Blocking IF1 expression by cotreatment with epigallocatechin-3-gallate (EGCG) increased apoptosis of HL60 cells. Upregulation of the mitochondrial citrate carrier shifted excess citrate to the cytosol for use in lipogenesis and for storage as triacylglycerol in lipid droplets (LDs). Accordingly, clozapine-treated HL60 cells and leukocytes from clozapine-treated patients contain more LDs than untreated cells. Since mitochondrial disturbances are described in the pathophysiology of schizophrenia, clozapine-induced mitohormesis is an excellent way to escape energy deficits and improve cell survival.<\/jats:p>","DOI":"10.3390\/cells13090762","type":"journal-article","created":{"date-parts":[[2024,5,2]],"date-time":"2024-05-02T08:42:57Z","timestamp":1714639377000},"page":"762","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Neuroreceptor Inhibition by Clozapine Triggers Mitohormesis and Metabolic Reprogramming in Human Blood Cells"],"prefix":"10.3390","volume":"13","author":[{"given":"Karin","family":"Fehsel","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Bergische Landstrasse 2, 40629 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Luise","family":"Bouvier","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Bergische Landstrasse 2, 40629 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9058-7743","authenticated-orcid":false,"given":"Loredana","family":"Capobianco","sequence":"additional","affiliation":[{"name":"Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7118-1994","authenticated-orcid":false,"given":"Paola","family":"Lunetti","sequence":"additional","affiliation":[{"name":"Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Klein","sequence":"additional","affiliation":[{"name":"Institute of Bio- and Geosciences, IBG-1: Biotechnology, Forschungszentrum J\u00fclich, Leo-Brandt-Stra\u00dfe, 52428 J\u00fclich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0704-5597","authenticated-orcid":false,"given":"Marko","family":"Oldiges","sequence":"additional","affiliation":[{"name":"Institute of Bio- and Geosciences, IBG-1: Biotechnology, Forschungszentrum J\u00fclich, Leo-Brandt-Stra\u00dfe, 52428 J\u00fclich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Majora","sequence":"additional","affiliation":[{"name":"Leibniz Research Institute for Environmental Medicine (IUF), Auf\u2019m Hennekamp 50, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"L\u00f6ffler","sequence":"additional","affiliation":[{"name":"Clinic for Psychiatry, Psychotherapy and Psychosomatics, Sana Klinikum Offenbach, Teaching Hospital of Goethe University, Starkenburgring 66, 63069 Offenbach, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1093\/schbul\/sbad066","article-title":"Review: Genes Involved in Mitochondrial Physiology Within 22q11.2 Deleted Region and Their Relevance to Schizophrenia","volume":"49","author":"Kolar","year":"2023","journal-title":"Schizophr. 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