{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T01:07:57Z","timestamp":1788570477791,"version":"build-2803163510"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:00:00Z","timestamp":1745798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p><jats:italic>Candida glabrata<\/jats:italic> is a prevalent opportunistic fungal pathogen in humans, and fluconazole (FLC) is one of the most commonly used antifungal agents. However, the molecular mechanisms underlying FLC tolerance in <jats:italic>C. glabrata<\/jats:italic> remain largely unexplored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>This study aims to identify novel mechanisms regulating FLC tolerance, with a particular focus on tunicamycin (TUN)-induced respiratory deficiency.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We employed three distinct experimental approaches to investigate the impact of TUN on FLC tolerance: (1) co-treatment with TUN and FLC, (2) exclusive exposure to TUN, and (3) induction of petite formation through alternative methods. Additionally, gene expression analyses were conducted to evaluate the regulation of key genes involved in the ergosterol biosynthesis pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our findings reveal that TUN exposure significantly abolishes FLC tolerance in <jats:italic>C. glabrata<\/jats:italic>, primarily through the induction of petite formation, which is characterized by mitochondrial dysfunction. Notably, TUN treatment resulted in the downregulation of critical ergosterol biosynthesis genes, including <jats:italic>ERG1<\/jats:italic> and <jats:italic>ERG11<\/jats:italic>, indicating a metabolic shift in response to endoplasmic reticulum (ER) stress. Furthermore, both TUN-induced and ethidium bromide-induced petites displayed cross-resistance to TUN and FLC but showed reduced tolerance to FLC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results underscore the pivotal role of TUN-induced ER stress in modulating FLC tolerance via respiratory deficiency and alterations in ergosterol metabolism. Our study emphasizes the importance of mitochondrial integrity in maintaining drug tolerance in <jats:italic>C. glabrata<\/jats:italic> and suggests potential therapeutic strategies targeting metabolic pathways associated with antifungal tolerance. A deeper understanding of these mechanisms may enhance our capacity to effectively combat fungal infections.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmicb.2025.1528341","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T05:29:50Z","timestamp":1745818190000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Uncovering the connection between tunicamycin-induced respiratory deficiency and reduced fluconazole tolerance in Candida glabrata"],"prefix":"10.3389","volume":"16","author":[{"given":"Lijun","family":"Zheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubo","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maoji","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linfeng","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangsheng","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,28]]},"reference":[{"key":"ref9001","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1128\/jb.100.1.370-376.1969","article-title":"Differential effect of respiratory inhibitors on ergosterol synthesis by Saccharomyces cerevisiae during adaptation to oxygen","volume":"100","author":"Adams","year":"1969","journal-title":"J Bacteriol"},{"key":"ref1","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1038\/s41579-019-0322-2","article-title":"Drug resistance and tolerance in fungi","volume":"18","author":"Berman","year":"2020","journal-title":"Nat. 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