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MICU1 confers protection from MCU-dependent manganese toxicity

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dc.contributor.author Wettmarshausen, Jennifer
dc.contributor.author Goh, Valerie
dc.contributor.author Huang, Kai-Ting
dc.contributor.author Arduino, Daniela M.
dc.contributor.author Tripathi, Utkarsh
dc.contributor.author Leimpek, Anja
dc.contributor.author Cheng, Yiming
dc.contributor.author Pittis, Alexandros, 1982-
dc.contributor.author Gabaldón Estevan, Juan Antonio, 1973-
dc.contributor.author Mokranjac, Dejana
dc.contributor.author Hajnóczky, György
dc.contributor.author Perocchi, Fabiana
dc.date.accessioned 2019-11-04T08:47:57Z
dc.date.available 2019-11-04T08:47:57Z
dc.date.issued 2018
dc.identifier.citation Wettmarshausen J, Goh V, Huang KT, Arduino DM, Tripathi U, Leimpek A et al. MICU1 confers protection from MCU-dependent manganese toxicity. Cell Rep. 2018;25(6):1425-35. DOI: 10.1016/j.celrep.2018.10.037
dc.identifier.issn 2211-1247
dc.identifier.uri http://hdl.handle.net/10230/42590
dc.description.abstract The mitochondrial calcium uniporter is a highly selective ion channel composed of species- and tissue-specific subunits. However, the functional role of each component still remains unclear. Here, we establish a synthetic biology approach to dissect the interdependence between the pore-forming subunit MCU and the calcium-sensing regulator MICU1. Correlated evolutionary patterns across 247 eukaryotes indicate that their co-occurrence may have conferred a positive fitness advantage. We find that, while the heterologous reconstitution of MCU and EMRE in vivo in yeast enhances manganese stress, this is prevented by co-expression of MICU1. Accordingly, MICU1 deletion sensitizes human cells to manganese-dependent cell death by disinhibiting MCU-mediated manganese uptake. As a result, manganese overload increases oxidative stress, which can be effectively prevented by NAC treatment. Our study identifies a critical contribution of MICU1 to the uniporter selectivity, with important implications for patients with MICU1 deficiency, as well as neurological disorders arising upon chronic manganese exposure.
dc.description.sponsorship We acknowledge support from the German Research Foundation (DFG) under the Emmy Noether Programme (PE 2053/1-1 to F.P. and J.W.), the Munich Center for Systems Neurology (SyNergy EXC 1010 to F.P.), the Juniorverbund in der Systemmedizin “mitOmics” (FKZ 01ZX1405B to V.G. and A.L.), The Bert L & N Kuggie Vallee Foundation (to F.P. and D.M.A.), the DFG (MO1944/1-2 to D.M.), the Spanish Ministry of Economy, Industry, and Competitiveness (MEIC; BFU2015-67107), the European Union’s Horizon 2020 research and innovation program under grant agreement ERC-2016-724173 (to T.G. and A.A.P.), and the NIH (RO1 GM102724 to G.H.).
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof Cell Reports. 2018;25(6):1425-35
dc.rights © 2018 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title MICU1 confers protection from MCU-dependent manganese toxicity
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1016/j.celrep.2018.10.037
dc.subject.keyword Mitochondria
dc.subject.keyword Calcium
dc.subject.keyword MCU
dc.subject.keyword MICU1
dc.subject.keyword Yeast
dc.subject.keyword Manganese
dc.subject.keyword Signaling
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2015-67107
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/724173
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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