{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T20:07:54Z","timestamp":1792526874550,"version":"4.5.0"},"reference-count":60,"publisher":"National Academy of Sciences","issue":"3","license":[{"start":{"date-parts":[[2020,6,6]],"date-time":"2020-06-06T00:00:00Z","timestamp":1591401600000},"content-version":"vor","delay-in-days":183,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2020,1,21]]},"abstract":"<jats:p>\n                    Drug resistance in fungal pathogens has risen steadily over the past decades due to long-term azole therapy or triazole usage in agriculture. Modification of the drug target protein to prevent drug binding is a major recognized route to induce drug resistance. However, mechanisms for nondrug target-induced resistance remain only loosely defined. Here, we explore the molecular mechanisms of multidrug resistance resulted from an efficient adaptation strategy for survival in drug environments in the human pathogen\n                    <jats:italic>Aspergillus fumigatus<\/jats:italic>\n                    . We show that mutants conferring multidrug resistance are linked with mitochondrial dysfunction induced by defects in heme A biosynthesis. Comparison of the gene expression profiles between the drug-resistant mutants and the parental wild-type strain shows that multidrug-resistant transporters, chitin synthases, and calcium-signaling-related genes are significantly up-regulated, while scavenging mitochondrial reactive oxygen species (ROS)-related genes are significantly down-regulated. The up-regulated-expression genes share consensus calcium-dependent serine threonine phosphatase-dependent response elements (the binding sites of calcium-signaling transcription factor CrzA). Accordingly, drug-resistant mutants show enhanced cytosolic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transients and persistent nuclear localization of CrzA. In comparison, calcium chelators significantly restore drug susceptibility and increase azole efficacy either in laboratory-derived or in clinic-isolated\n                    <jats:italic>A. fumigatus<\/jats:italic>\n                    strains. Thus, the mitochondrial dysfunction as a fitness cost can trigger calcium signaling and, therefore, globally up-regulate a series of embedding calcineurin-dependent\u2013response-element genes, leading to antifungal resistance. These findings illuminate how fitness cost affects drug resistance and suggest that disruption of calcium signaling might be a promising therapeutic strategy to fight against nondrug target-induced drug resistance.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1911560116","type":"journal-article","created":{"date-parts":[[2019,12,6]],"date-time":"2019-12-06T18:55:33Z","timestamp":1575658533000},"page":"1711-1721","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":86,"title":["Mitochondrial dysfunctions trigger the calcium signaling-dependent fungal multidrug resistance"],"prefix":"10.1073","volume":"117","author":[{"given":"Yeqi","family":"Li","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 210023 Nanjing, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 210023 Nanjing, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 210023 Nanjing, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongchen","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 210023 Nanjing, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolei","family":"Wei","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 210023 Nanjing, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiying","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Jinling Hospital, School of Medicine, Nanjing University, 210002 Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2891-7326","authenticated-orcid":false,"given":"Ling","family":"Lu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 210023 Nanjing, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2019,12,6]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1056\/NEJMra0808853","article-title":"Aspergillosis","volume":"360","author":"Segal B. 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