{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T05:32:18Z","timestamp":1780378338479,"version":"3.54.1"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,20]],"date-time":"2021-05-20T00:00:00Z","timestamp":1621468800000},"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:p>The effects of the interplay of copper(II) and manganese(II) ions on growth, morphology and itaconic acid formation was investigated in a high-producing strain of <jats:italic>Aspergillus terreus<\/jats:italic> (NRRL1960), using carbon sources metabolized either mainly via glycolysis (<jats:sc>D<\/jats:sc>-glucose, <jats:sc>D<\/jats:sc>-fructose) or primarily via the pentose phosphate shunt (<jats:sc>D<\/jats:sc>-xylose, <jats:sc>L<\/jats:sc>-arabinose). Limiting Mn<jats:sup>2+<\/jats:sup> concentration in the culture broth is indispensable to obtain high itaconic acid yields, while in the presence of higher Mn<jats:sup>2+<\/jats:sup> concentrations yield decreases and biomass formation is favored. However, this low yield in the presence of high Mn<jats:sup>2+<\/jats:sup> ion concentrations can be mitigated by increasing the Cu<jats:sup>2+<\/jats:sup> concentration in the medium when <jats:sc>D<\/jats:sc>-glucose or <jats:sc>D<\/jats:sc>-fructose is the growth substrate, whereas this effect was at best modest during growth on <jats:sc>D<\/jats:sc>-xylose or <jats:sc>L<\/jats:sc>-arabinose. <jats:italic>A. terreus<\/jats:italic> displays a high tolerance to Cu<jats:sup>2+<\/jats:sup> which decreased when Mn<jats:sup>2+<\/jats:sup> availability became increasingly limiting. Under such conditions biomass formation on <jats:sc>D<\/jats:sc>-glucose or <jats:sc>D<\/jats:sc>-fructose could be sustained at concentrations up to 250 mg L<jats:sup>\u20131<\/jats:sup> Cu<jats:sup>2+<\/jats:sup>, while on <jats:sc>D<\/jats:sc>-xylose- or <jats:sc>L<\/jats:sc>-arabinose biomass formation was completely inhibited at 100 mg L<jats:sup>\u20131<\/jats:sup>. High (&amp;gt;75%) specific molar itaconic acid yields always coincided with an \u201coverflow-associated\u201d morphology, characterized by small compact pellets (&amp;lt;250 \u03bcm diameter) and short chains of \u201cyeast-like\u201d cells that exhibit increased diameters relative to the elongated cells in growing filamentous hyphae. At low concentrations (\u22641 mg L<jats:sup>\u20131<\/jats:sup>) of Cu<jats:sup>2+<\/jats:sup> ions, manganese deficiency did not prevent filamentous growth. Mycelial- and cellular morphology progressively transformed into the typical overflow-associated one when external Cu<jats:sup>2+<\/jats:sup> concentrations increased, irrespective of the available Mn<jats:sup>2+<\/jats:sup>. Our results indicate that copper ions are relevant for overflow metabolism and should be considered when optimizing itaconic acid fermentation in <jats:italic>A. terreu<\/jats:italic>s.<\/jats:p>","DOI":"10.3389\/fmicb.2021.680420","type":"journal-article","created":{"date-parts":[[2021,5,20]],"date-time":"2021-05-20T05:50:45Z","timestamp":1621489845000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Carbon-Source Dependent Interplay of Copper and Manganese Ions Modulates the Morphology and Itaconic Acid Production in Aspergillus terreus"],"prefix":"10.3389","volume":"12","author":[{"given":"Erzs\u00e9bet","family":"S\u00e1ndor","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Istv\u00e1n S.","family":"Koll\u00e1th","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erzs\u00e9bet","family":"Fekete","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivien","family":"B\u00edr\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Flipphi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e9la","family":"Kov\u00e1cs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian P.","family":"Kubicek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Levente","family":"Karaffa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1104\/pp.10\u00a0\u00b1\u00a06.088609","article-title":"Manganese deficiency in Chlamydomonas results in loss of photosystem II and MnSOD function, sensitivity to peroxides, and secondary phosphorus and iron deficiency.","volume":"143","author":"Allen","year":"2007","journal-title":"Plant Physiol."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/membranes10090242","article-title":"Cu homeostasis in bacteria: the ins and outs.","volume":"10","author":"Andrei","year":"2020","journal-title":"Membranes"},{"key":"B3","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1007\/s10123-019-00081-5","article-title":"New insights into copper homeostasis in filamentous fungi.","volume":"23","author":"Antsotegi-Uskola","year":"2020","journal-title":"Int. Microbiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1002\/jobm.3620300503","article-title":"Acremonium chrysogenum differentiation and biosynthesis of cephalosporin.","volume":"30","author":"Bartoshevich","year":"1990","journal-title":"J. Basic Microbiol."},{"key":"B5","author":"Batti","year":"1963","journal-title":"Process for the Production of Itaconic Acid."},{"key":"B6","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/0092-8674(92)90270-m","article-title":"The structure of human mitochondrial manganese superoxide dismutase reveals a novel tetrameric interface of two 4-helix bundles.","volume":"71","author":"Borgstahl","year":"1992","journal-title":"Cell"},{"key":"B7","first-page":"595","article-title":"Transcriptional regulation of MnSOD by manganese in the liver of manganese-deficient mice and during rat development.","volume":"28","author":"Borrello","year":"1992","journal-title":"Biochem. Intern."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/biom10020330","article-title":"NAD+ metabolism and regulation: lessons from yeast.","volume":"10","author":"Croft","year":"2020","journal-title":"Biomolecules"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s13205-018-1151-0","article-title":"World market and biotechnological production of itaconic acid.","volume":"8","author":"Cunha da Cruz","year":"2018","journal-title":"3 Biotech."},{"key":"B10","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1099\/00221287-65-3-259","article-title":"Induction of yeastlike development in Aspergillus parasiticus.","volume":"65","author":"Detroy","year":"1971","journal-title":"Microbiology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1111\/mmi.12653","article-title":"Iron and copper as virulence modulators in human fungal pathogens.","volume":"93","author":"Ding","year":"2014","journal-title":"Mol. Microbiol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/j.enzmictec.2007.10.012","article-title":"Effects of dissolved carbon dioxide on growth, nutrient consumption, cephalosporin C synthesis and morphology of Acremonium chrysogenum in batch cultures.","volume":"42","author":"El-Sabbagh","year":"2008","journal-title":"Enzyme Microb. Technol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1007\/s00203-002-0491-496","article-title":"Regulation of the intracellular beta-galactosidase activity of Aspergillus nidulans.","volume":"179","author":"Fekete","year":"2002","journal-title":"Arch. Microbiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.mito.2014.02.011","article-title":"Mitochondria and copper homeostasis in plants.","volume":"19","author":"Garcia","year":"2014","journal-title":"Mitochondrion"},{"key":"B15","doi-asserted-by":"publisher","first-page":"18945","DOI":"10.1074\/jbc.R115.649129","article-title":"Copper at the fungal pathogen-host Axis.","volume":"290","author":"Garc\u00eda-Santamarina","year":"2015","journal-title":"J. Biol. Chem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1093\/emboj\/20.4.638","article-title":"Bovine \u03b11, 3-galactosyltransferase catalytic domain structure and its relationship with ABO histo-blood group and glycosphingolipid glycosyltransferases.","volume":"20","author":"Gastinel","year":"2001","journal-title":"EMBO J."},{"key":"B17","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1007\/BF00169929","article-title":"Factors affecting the growth form of Aspergillus terreus NRRL 1960 in relation to itaconic acid fermentation.","volume":"44","author":"Gyamerah","year":"1995","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"37","DOI":"10.19026\/crjbs.7.5205","article-title":"Itaconic acid production by microorganisms: a review.","volume":"7","author":"Hajian","year":"2015","journal-title":"Curr. Res. J. Biol. Sci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"10005","DOI":"10.1007\/s00253-014-6047-2","article-title":"Influence of the pH on the itaconic acid production with Aspergillus terreus.","volume":"98","author":"Hevekerl","year":"2014","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"3513","DOI":"10.1099\/00221287-133-12-3513","article-title":"A specific transport system for manganese in the filamentous fungus Aspergillus niger.","volume":"133","author":"Hockertz","year":"1987","journal-title":"Microbiology"},{"key":"B21","doi-asserted-by":"publisher","first-page":"7937","DOI":"10.1007\/s00253-015-6735-6","article-title":"A deficiency of manganese ions in the presence of high sugar concentrations is the critical parameter for achieving high yields of itaconic acid by Aspergillus terreus.","volume":"99","author":"Karaffa","year":"2015","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2889","DOI":"10.1007\/s00253-018-09607-9","article-title":"Citric acid and itaconic acid accumulation: variations of the same story?","volume":"103","author":"Karaffa","year":"2019","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1016\/S0032-9592(97)00003-4","article-title":"Methionine enhances sugar consumption, fragmentation, vacuolation and cephalosporin-C production in Acremonium chrysogenum.","volume":"32","author":"Karaffa","year":"1997","journal-title":"Process Biochem."},{"key":"B24","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1093\/glycob\/cwx028","article-title":"GfsA is a \u03b21,5-galactofuranosyltransferase involved in the biosynthesis of the galactofuran side chain of fungal-type galactomannan in Aspergillus fumigatus.","volume":"27","author":"Katafuchi","year":"2017","journal-title":"Glycobiology"},{"key":"B25","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1007\/BF00422301","article-title":"Influence of manganese on morphology and cell wall composition of Aspergillus niger during citric acid fermentation.","volume":"128","author":"Kisser","year":"1980","journal-title":"Arch. Microbiol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2783","DOI":"10.1091\/mbc.e02-02-0075","article-title":"Dissection of transient oxidative stress response in Saccharomyces cerevisiae by using DNA microarrays.","volume":"13","author":"Koerkamp","year":"2002","journal-title":"Mol. Biol. Cell"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.01589","article-title":"Manganese deficiency is required for high itaconic acid production from D-xylose in Aspergillus terreus.","volume":"10","author":"Koll\u00e1th","year":"2019","journal-title":"Front. Microbiol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1111\/mmi.12416","article-title":"gfsA encodes a novel galactofuranosyltransferase involved in biosynthesis of galactofuranose antigen of O-glycan in Aspergillus nidulans and Aspergillus fumigatus.","volume":"90","author":"Komachi","year":"2013","journal-title":"Mol. Microbiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/0168-1656(96)01400-9","article-title":"Effect of oxygen on the respiratory system and cephalosporin-C production in Acremonium chrysogenum.","volume":"48","author":"Kozma","year":"1996","journal-title":"J. Biotechnol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1336","DOI":"10.1128\/AEM.50.5.1336-1338.1985","article-title":"Aconitase and citric acid fermentation by Aspergillus niger.","volume":"50","author":"Kubicek","year":"1985","journal-title":"Appl. Environ. Microbiol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1007\/s00253-012-4221-y","article-title":"Microbial production of itaconic acid: developing a stable platform for high product concentrations.","volume":"96","author":"Kuenz","year":"2012","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"3901","DOI":"10.1007\/s00253-018-8895-7","article-title":"Biotechnological production of itaconic acid\u2014things you have to know.","volume":"102","author":"Kuenz","year":"2018","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21144932","article-title":"Copper homeostasis in mammals, with emphasis on secretion and excretion. A Review.","volume":"21","author":"Linder","year":"2020","journal-title":"Intern. J. Mol. Sci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"17921","DOI":"10.1074\/jbc.M312720200","article-title":"Structure of Kre2p\/Mnt1p: a yeast \u03b11, 2-mannosyltransferase involved in mannoprotein biosynthesis.","volume":"279","author":"Lobsanov","year":"2004","journal-title":"J. Biol. Chem."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1080\/21505594.2020.1809324","article-title":"Cu transporter protein CrpF protects against Cu-induced toxicity in Fusarium oxysporum.","volume":"11","author":"Lorenzo-Guti\u00e9rrez","year":"2020","journal-title":"Virulence"},{"key":"B36","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1111\/j.1574-6968.1981.tb07630.x","article-title":"Malate dehydrogenase isoenzymes in Aspergillus niger.","volume":"12","author":"Ma","year":"1981","journal-title":"FEMS Microbiol. Lett."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0158683","article-title":"Host-imposed copper poisoning impacts fungal micronutrient acquisition during systemic Candida albicans infections.","volume":"11","author":"Mackie","year":"2016","journal-title":"PLoS One"},{"key":"B38","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1139\/m84-003","article-title":"Pyruvate kinase from Aspergillus niger: a regulatory enzyme in glycolysis?","volume":"30","author":"Meixner-Monori","year":"1984","journal-title":"Can. J. Microbiol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"8799","DOI":"10.1007\/s00253-018-9325-6","article-title":"High oxygen tension increases itaconic acid accumulation, glucose consumption, and the expression and activity of alternative oxidase in Aspergillus terreus.","volume":"102","author":"Moln\u00e1r","year":"2018","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/S0005-2736(97)00032-1","article-title":"Uptake and export of citric acid by Aspergillus niger is reciprocally regulated by manganese ions.","volume":"1326","author":"Netik","year":"1997","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"B41","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1007\/s00253-009-2132-3","article-title":"Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus.","volume":"84","author":"Okabe","year":"2009","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"38388","DOI":"10.1074\/jbc.M105395200","article-title":"Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu, Zn-SOD in mitochondria.","volume":"276","author":"Okado-Matsumoto","year":"2001","journal-title":"J. Biol. Chem."},{"key":"B43","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1002\/bit.260440513","article-title":"Hyphal vacuolation and fragmentation in Penicillium chrysogenum.","volume":"44","author":"Paul","year":"1994","journal-title":"Biotechnol. Bioeng."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/BFb0102278","article-title":"Characterisation of mycelial morphology using image analysis.","volume":"60","author":"Paul","year":"1998","journal-title":"Relat. Morphol. Process Perform."},{"key":"B45","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1038\/84168","article-title":"Crystal structure of the retaining galactosyltransferase LgtC from Neisseria meningitidis in complex with donor and acceptor sugar analogs.","volume":"8","author":"Persson","year":"2001","journal-title":"Nat. Struct. Biol."},{"key":"B46","doi-asserted-by":"crossref","first-page":"6107","DOI":"10.1016\/S0021-9258(19)41165-4","article-title":"Isolation and characterization of a manganese-containing superoxide dismutase from yeast.","volume":"250","author":"Ravindranath","year":"1975","journal-title":"J. Biol. Chem."},{"key":"B47","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1007\/s10295-003-0049-x","article-title":"Hemicellulose bioconversion.","volume":"30","author":"Saha","year":"2003","journal-title":"J. Industr. Microbiol. Biotechnol."},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1002\/btpr.2939","article-title":"Efficient itaconic acid production by Aspergillus terreus: overcoming the strong inhibitory effect of manganese.","volume":"36","author":"Saha","year":"","journal-title":"Biotechnol. Prog."},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcab.2019.01.054","article-title":"Phosphate limitation alleviates the inhibitory effect of manganese on itaconic acid production by Aspergillus terreus.","volume":"18","author":"Saha","year":"","journal-title":"Biocatalys. Agric. Biotechnol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1002\/btpr.2485","article-title":"Production of itaconic acid from pentose sugars by Aspergillus terreus.","volume":"33","author":"Saha","year":"2017","journal-title":"Biotechnol. Prog."},{"key":"B51","author":"Schweiger","year":"1958","journal-title":"Production of Citric Acid by Fermentation."},{"key":"B52","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1146\/annurev-micro-030117-020444","article-title":"Copper acquisition and utilization in fungi.","volume":"71","author":"Smith","year":"2017","journal-title":"Annu. Rev. Microbiol."},{"key":"B53","doi-asserted-by":"crossref","first-page":"4793","DOI":"10.1016\/S0021-9258(19)43735-6","article-title":"Mitochondrial superoxide dismutase site of synthesis and intramitochondrial localization.","volume":"248","author":"Weisiger","year":"1973","journal-title":"J. Biol. Chem."},{"key":"B54","doi-asserted-by":"publisher","first-page":"2174","DOI":"10.1016\/j.celrep.2017.05.075","article-title":"Aspergillus fumigatus copper export machinery and reactive oxygen intermediate defense counter host copper-mediated oxidative antimicrobial offense.","volume":"19","author":"Wiemann","year":"2017","journal-title":"Cell Rep."},{"key":"B55","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/0167-4838(89)90058-7","article-title":"Synthesis and processing of the precursor for human mangano-superoxide dismutase.","volume":"994","author":"Wispe","year":"1989","journal-title":"Biochim. Biophys. Acta Protein Struct. Mol. Enzymol."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.680420\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,20]],"date-time":"2021-05-20T05:50:49Z","timestamp":1621489849000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.680420\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,20]]},"references-count":55,"alternative-id":["10.3389\/fmicb.2021.680420"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2021.680420","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,20]]},"article-number":"680420"}}