{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:42:18Z","timestamp":1792651338706,"version":"4.5.0"},"reference-count":28,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T00:00:00Z","timestamp":1792540800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T00:00:00Z","timestamp":1792540800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004497","name":"Onderzoeksraad, KU Leuven","doi-asserted-by":"publisher","award":["C14\/22\/075"],"award-info":[{"award-number":["C14\/22\/075"]}],"id":[{"id":"10.13039\/501100004497","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001704","name":"European Society of Clinical Microbiology and Infectious Diseases","doi-asserted-by":"publisher","award":["19155"],"award-info":[{"award-number":["19155"]}],"id":[{"id":"10.13039\/501100001704","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"abstract":"<jats:p>\n                    Antimicrobial resistance is an escalating global concern with the human fungal pathogen,\n                    <jats:italic>Candida albicans<\/jats:italic>\n                    , increasingly exhibiting resistance to fluconazole (FLC). Together with the high mortality associated with bloodstream infections, this growing resistance contributed to the classification of\n                    <jats:italic>C. albicans<\/jats:italic>\n                    as a critical priority pathogen by the World Health Organisation (WHO). Notably,\n                    <jats:italic>C. albicans<\/jats:italic>\n                    can survive high concentrations of fluconazole (FLC) through a phenomenon termed tolerance, which is different from resistance as tolerant cells grow slowly. Tolerance is considered a precursor to resistance development. Previous work from our laboratory demonstrated that intracellular iron homeostasis, particularly the mobilisation of vacuolar iron stores, modulates the synergistic interaction between doxycycline, an iron chelator, and FLC. Building on this, we hypothesised that mitochondrial iron plays a central role in determining FLC susceptibility, supported by emerging links between mitochondrial function, iron metabolism, and azole response. Mitochondrial iron import is mediated by\n                    <jats:italic>MRS4<\/jats:italic>\n                    , after which iron is primarily incorporated into iron\u2013sulfur clusters and haem. Here, we investigated the role of mitochondrial iron import via\n                    <jats:italic>MRS4<\/jats:italic>\n                    in azole susceptibility phenotypes, including tolerance, synergy and cidality. We demonstrate that\n                    <jats:italic>MRS4<\/jats:italic>\n                    is essential for FLC tolerance under iron\u2010chelating conditions, despite minimal effects on minimal inhibitory concentration or drug synergy. Absence of\n                    <jats:italic>MRS4<\/jats:italic>\n                    results in mitochondrial dysfunction and accumulation of toxic sterol intermediates during FLC treatment. Collectively, our findings reveal that mitochondrial iron homeostasis critically governs azole tolerance and highlights toxic sterol accumulation as a driver of fungicidal outcomes.\n                  <\/jats:p>","DOI":"10.1111\/febs.70773","type":"journal-article","created":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:21:07Z","timestamp":1792650067000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial iron homeostasis is required for azole tolerance in\n                    <i>Candida albicans<\/i>"],"prefix":"10.1111","author":[{"given":"Wouter","family":"Van Genechten","sequence":"first","affiliation":[{"name":"Laboratory for Molecular Cell Biology, Department Biology KU Leuven  Belgium"},{"name":"One Health Institute KU Leuven  Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gauthier","family":"Cornips","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Cell Biology, Department Biology KU Leuven  Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martine","family":"De Jonge","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Cell Biology, Department Biology KU Leuven  Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudy","family":"Vergauwen","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Cell Biology, Department Biology KU Leuven  Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1542-897X","authenticated-orcid":false,"given":"Patrick","family":"Van Dijck","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Cell Biology, Department Biology KU Leuven  Belgium"},{"name":"One Health Institute KU Leuven  Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,21]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"Organization GWHWHO fungal priority pathogens list to guide research development and public health action. 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