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.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.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.doi http://dx.doi.org/10.1016/j.celrep.2018.10.037
- dc.identifier.issn 2211-1247
- dc.identifier.uri http://hdl.handle.net/10230/42590
- dc.language.iso eng
- dc.publisher Elsevier
- dc.relation.ispartof Cell Reports. 2018;25(6):1425-35
- dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2015-67107
- dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/724173
- 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.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by/4.0/
- 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.title MICU1 confers protection from MCU-dependent manganese toxicity
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion