{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:59:53Z","timestamp":1791295193392,"version":"4.1.0"},"reference-count":75,"publisher":"The Company of Biologists","issue":"5","license":[{"start":{"date-parts":[[2020,9,2]],"date-time":"2020-09-02T00:00:00Z","timestamp":1599004800000},"content-version":"vor","delay-in-days":1594,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0"}],"funder":[{"DOI":"10.13039\/501100001648","name":"European Foundation for the Study of Diabetes","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001648","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,5,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Friedreich ataxia is a neurodegenerative disease caused by a GAA triplet repeat expansion in the first intron of the frataxin gene, which results in reduced expression levels of the corresponding protein. Despite numerous animal and cellular models, therapeutic options that mechanistically address impaired frataxin expression are lacking. Here, we have developed a new mammalian cell model employing the Cre\/loxP recombination system to induce a homozygous or heterozygous frataxin knockout in mouse embryonic fibroblasts. Induction of Cre-mediated disruption by tamoxifen was successfully tested on RNA and protein levels. After loss of frataxin protein, cell division, aconitase activity and oxygen consumption rates were found to be decreased, while ROS production was increased in the homozygous state. By contrast, in the heterozygous state no such changes were observed. A time-resolved analysis revealed the loss of aconitase activity as an initial event after induction of complete frataxin deficiency, followed by secondarily elevated ROS production and a late increase in iron content. Initial impairments of oxygen consumption and ATP production were found to be compensated in the late state and seemed to play a minor role in Friedreich ataxia pathophysiology. In conclusion and as predicted from its proposed role in iron sulfur cluster (ISC) biosynthesis, disruption of frataxin primarily causes impaired function of ISC-containing enzymes, whereas other consequences, including elevated ROS production and iron accumulation, appear secondary. These parameters and the robustness of the newly established system may additionally be used for a time-resolved study of pharmacological candidates in a HTS manner.<\/jats:p>","DOI":"10.1242\/bio.017004","type":"journal-article","created":{"date-parts":[[2016,4,23]],"date-time":"2016-04-23T03:13:34Z","timestamp":1461381214000},"page":"654-661","source":"Crossref","is-referenced-by-count":21,"title":["Time-resolved functional analysis of acute impairment of <i>frataxin<\/i> expression in an inducible cell model of Friedreich ataxia"],"prefix":"10.1242","volume":"5","author":[{"given":"D\u00f6rte","family":"Poburski","sequence":"first","affiliation":[{"name":"Institute of Nutrition, Friedrich Schiller University (FSU) Jena, Dornburgerstra\u00dfe 24, Jena D-07743, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josefine Barbara","family":"Boerner","sequence":"additional","affiliation":[{"name":"Institute of Nutrition, Friedrich Schiller University (FSU) Jena, Dornburgerstra\u00dfe 24, Jena D-07743, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Koenig","sequence":"additional","affiliation":[{"name":"Laboratoire de G\u00e9n\u00e9tique de Maladies Rares EA7402, Institut Universitaire de Recherche Clinique, Universit\u00e9 de Montpellier, Montpellier F-34093, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Ristow","sequence":"additional","affiliation":[{"name":"Institute of Nutrition, Friedrich Schiller University (FSU) Jena, Dornburgerstra\u00dfe 24, Jena D-07743, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7785-5846","authenticated-orcid":false,"given":"Ren\u00e9","family":"Thierbach","sequence":"additional","affiliation":[{"name":"Institute of Nutrition, Friedrich Schiller University (FSU) Jena, Dornburgerstra\u00dfe 24, Jena D-07743, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2016,4,22]]},"reference":[{"key":"2021042423260133200_BIO017004C1","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1016\/j.ygeno.2006.06.015","article-title":"GAA repeat expansion mutation mouse models of Friedreich ataxia exhibit oxidative stress leading to progressive neuronal and cardiac pathology","volume":"88","author":"Al-Mahdawi","year":"2006","journal-title":"Genomics"},{"key":"2021042423260133200_BIO017004C2","doi-asserted-by":"publisher","first-page":"1709","DOI":"10.1126\/science.276.5319.1709","article-title":"Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin","volume":"276","author":"Babcock","year":"1997","journal-title":"Science"},{"key":"2021042423260133200_BIO017004C3","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1186\/1741-7015-9-112","article-title":"Friedreich's ataxia: the vicious circle hypothesis revisited","volume":"9","author":"Bayot","year":"2011","journal-title":"BMC Med."},{"key":"2021042423260133200_BIO017004C4","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1182\/blood-2006-12-065433","article-title":"Selective iron chelation in Friedreich ataxia: biologic and clinical implications","volume":"110","author":"Boddaert","year":"2007","journal-title":"Blood"},{"key":"2021042423260133200_BIO017004C5","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","article-title":"A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding","volume":"72","author":"Bradford","year":"1976","journal-title":"Anal. 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