Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-8795
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dc.contributor.authorWolf, Christina-
dc.contributor.authorPouya, Alireza-
dc.contributor.authorBitar, Sara-
dc.contributor.authorPfeiffer, Annika-
dc.contributor.authorBueno, Diones-
dc.contributor.authorRojas-Charry, Liliana-
dc.contributor.authorArndt, Sabine-
dc.contributor.authorGomez-Zepeda, David-
dc.contributor.authorTenzer, Stefan-
dc.contributor.authorDal Bello, Federica-
dc.contributor.authorVianello, Caterina-
dc.contributor.authorRitz, Sandra-
dc.contributor.authorSchwirz, Jonas-
dc.contributor.authorDobrindt, Kristina-
dc.contributor.authorPeitz, Michael-
dc.contributor.authorHanschmann, Eva-Maria-
dc.contributor.authorMencke, Pauline-
dc.contributor.authorBoussaad, Ibrahim-
dc.contributor.authorSilies, Marion-
dc.contributor.authorBrüstle, Oliver-
dc.contributor.authorGiacomello, Marta-
dc.contributor.authorKrüger, Rejko-
dc.contributor.authorMethner, Axel-
dc.date.accessioned2023-02-10T09:23:13Z-
dc.date.available2023-02-10T09:23:13Z-
dc.date.issued2022-
dc.identifier.urihttps://openscience.ub.uni-mainz.de/handle/20.500.12030/8811-
dc.description.abstractCharcot-Marie-Tooth (CMT) disease 4A is an autosomal-recessive polyneuropathy caused by mutations of ganglioside-induced differentiation-associated protein 1 (GDAP1), a putative glutathione transferase, which affects mitochondrial shape and alters cellular Ca2+ homeostasis. Here, we identify the underlying mechanism. We found that patient-derived motoneurons and GDAP1 knockdown SH-SY5Y cells display two phenotypes: more tubular mitochondria and a metabolism characterized by glutamine dependence and fewer cytosolic lipid droplets. GDAP1 interacts with the actin-depolymerizing protein Cofilin-1 and beta-tubulin in a redox-dependent manner, suggesting a role for actin signaling. Consistently, GDAP1 loss causes less F-actin close to mitochondria, which restricts mitochondrial localization of the fission factor dynamin-related protein 1, instigating tubularity. GDAP1 silencing also disrupts mitochondria-ER contact sites. These changes result in lower mitochondrial Ca2+ levels and inhibition of the pyruvate dehydrogenase complex, explaining the metabolic changes upon GDAP1 loss of function. Together, our findings reconcile GDAP1-associated phenotypes and implicate disrupted actin signaling in CMT4A pathophysiology.en_GB
dc.description.sponsorshipGefördert durch die Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 491381577de
dc.language.isoengde
dc.rightsCC BY*
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.subject.ddc610 Medizinde_DE
dc.subject.ddc610 Medical sciencesen_GB
dc.titleGDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeletonen_GB
dc.typeZeitschriftenaufsatzde
dc.identifier.doihttp://doi.org/10.25358/openscience-8795-
jgu.type.dinitypearticleen_GB
jgu.type.versionPublished versionde
jgu.type.resourceTextde
jgu.organisation.departmentFB 04 Medizinde
jgu.organisation.number2700-
jgu.organisation.nameJohannes Gutenberg-Universität Mainz-
jgu.rights.accessrightsopenAccess-
jgu.journal.titleCommunications biologyde
jgu.journal.volume5de
jgu.pages.alternative541de
jgu.publisher.year2022-
jgu.publisher.nameBioMed Centralde
jgu.publisher.placeLondonde
jgu.publisher.issn2399-3642de
jgu.organisation.placeMainz-
jgu.subject.ddccode610de
jgu.publisher.doi10.1038/s42003-022-03487-6de
jgu.organisation.rorhttps://ror.org/023b0x485-
jgu.subject.dfgLebenswissenschaftende
Appears in collections:DFG-491381577-G

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