{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:27:03Z","timestamp":1789000023678,"version":"build-2803163510"},"reference-count":66,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2023,12,12]],"date-time":"2023-12-12T00:00:00Z","timestamp":1702339200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,12,12]],"date-time":"2023-12-12T00:00:00Z","timestamp":1702339200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"HHS | NIH | National Institute of Dental and Craniofacial Research","award":["R01DE030130"],"award-info":[{"award-number":["R01DE030130"]}]},{"name":"HHS | National Institutes of Health","award":["FHL145914A"],"award-info":[{"award-number":["FHL145914A"]}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["937591"],"award-info":[{"award-number":["937591"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2023,12,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Although crucial for cellular functioning, iron is toxic when present in excess. Iron overload can create a labile iron pool (LIP) that harms the mitochondrion, resulting in disruption of oxidative respiration. Fungal pathogen\n            <jats:italic>C. albicans<\/jats:italic>\n            possesses an unconventional terminal oxidase [alternative oxidase (AOX)] that can disrupt the electron transport chain to remove excess electrons, generated from various stressors, to shield the respiratory apparatus. Here, we identify a novel role for AOX under high iron, whereby it works as \u201csafety valve\u201d to protect the mitochondrion from high iron-induced reactive oxygen species (ROS).\n            <jats:italic>C. albicans<\/jats:italic>\n            showed pronounced metabolic flexibility to environmental iron, ranging from 1 to 500 \u00b5M. High iron significantly increased intracellular iron, LIP, and levels of cellular ROS. Expression of both\n            <jats:italic>AOX1\/2<\/jats:italic>\n            was induced by iron, and cells lacking Aox1\/2 showed high levels of mitochondrial ROS as well as significant growth defect under high iron. Thus, Aox1\/2 helps mitigate the negative effects of iron. Furthermore, iron-induced expression of\n            <jats:italic>AOX1\/2<\/jats:italic>\n            was intermittent, thus preventing ATP loss despite AOX being non-proton motive. Mitochondrial oxygen consumption rate (OCR) was significantly higher (62.8%) under high iron conditions. Contribution of Aox1\/2 was greater toward this high OCR, compared to their contribution in low iron conditions. Lastly, enhanced virulence of\n            <jats:italic>C. albicans<\/jats:italic>\n            that is observed for wild-type cells under high iron was lost when fungal cells lacking\n            <jats:italic>AOX1\/2<\/jats:italic>\n            were used for murine infection. Thus, AOX is crucial for preserving mitochondrial function for survival in a high iron host.\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              The yeast\n              <jats:italic>C. albicans<\/jats:italic>\n              exhibits metabolic flexibility for adaptability to host niches with varying availability of nutrients including essential metals like iron. For example, blood is iron deplete, while the oral cavity and the intestinal lumen are considered iron replete. We show here that\n              <jats:italic>C. albicans<\/jats:italic>\n              can tolerate very high levels of environmental iron, despite an increase in high iron-induced reactive oxygen species (ROS) that it mitigates with the help of a unique oxidase, known as alternative oxidase (AOX). High iron induces\n              <jats:italic>AOX1\/2<\/jats:italic>\n              that limits mitochondrial accumulation of ROS. Genetic elimination of\n              <jats:italic>AOX1\/2<\/jats:italic>\n              resulted in diminished virulence during oropharyngeal candidiasis in high iron mice. Since human mitochondria lack AOX protein, it represents a unique target for treatment of fungal infections.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/spectrum.02157-23","type":"journal-article","created":{"date-parts":[[2023,11,6]],"date-time":"2023-11-06T13:01:03Z","timestamp":1699275663000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":20,"title":["Alternative oxidase promotes high iron tolerance in\n            <i>Candida albicans<\/i>"],"prefix":"10.1128","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5337-2594","authenticated-orcid":false,"given":"Rishabh","family":"Sharma","sequence":"first","affiliation":[{"name":"Oral Microbiome Research Laboratory, Kornberg School of Dentistry, Temple University , Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew 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