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dc.contributor.author Kohlschmidt, Nicolai
dc.contributor.author Elbracht, Miriam
dc.contributor.author Czech, Artur
dc.contributor.author Häusler, Martin
dc.contributor.author Phan, Vietxuan
dc.contributor.author Töpf, Ana
dc.contributor.author Huang, Kai-Ting
dc.contributor.author Bartok, Adam
dc.contributor.author Eggermann, Katja
dc.contributor.author Zippel, Stephanie
dc.contributor.author Eggermann, Thomas
dc.contributor.author Freier, Erik
dc.contributor.author Groß, Claudia
dc.contributor.author Lochmüller, Hanns
dc.contributor.author Horvath, Rita
dc.contributor.author Hajnóczky, György
dc.contributor.author Weis, Joachim
dc.contributor.author Roos, Andreas
dc.date.accessioned 2022-06-10T10:11:32Z
dc.date.available 2022-06-10T10:11:32Z
dc.date.issued 2021
dc.identifier.citation Kohlschmidt N, Elbracht M, Czech A, Häusler M, Phan V, Töpf A et al. Molecular pathophysiology of human MICU1 deficiency. Neuropathol Appl Neurobiol. 2021 Oct;47(6):840-855. DOI:10.1111/nan.12694
dc.identifier.issn 0305-1846
dc.identifier.uri http://hdl.handle.net/10230/53447
dc.description.abstract Aims: MICU1 encodes the gatekeeper of the mitochondrial Ca2+ uniporter, MICU1 and biallelic loss-of-function mutations cause a complex, neuromuscular disorder in children. Although the role of the protein is well understood, the precise molecular pathophysiology leading to this neuropaediatric phenotype has not been fully elucidated. Here we aimed to obtain novel insights into MICU1 pathophysiology. Methods: Molecular genetic studies along with proteomic profiling, electron-, light- and Coherent anti-Stokes Raman scattering microscopy and immuno-based studies of protein abundances and Ca2+ transport studies were employed to examine the pathophysiology of MICU1 deficiency in humans. Results: We describe two patients carrying MICU1 mutations, two nonsense (c.52C>T; p.(Arg18*) and c.553C>T; p.(Arg185*)) and an intragenic exon 2-deletion presenting with ataxia, developmental delay and early onset myopathy, clinodactyly, attention deficits, insomnia and impaired cognitive pain perception. Muscle biopsies revealed signs of dystrophy and neurogenic atrophy, severe mitochondrial perturbations, altered Golgi structure, vacuoles and altered lipid homeostasis. Comparative mitochondrial Ca2+ transport and proteomic studies on lymphoblastoid cells revealed that the [Ca2+ ] threshold and the cooperative activation of mitochondrial Ca2+ uptake were lost in MICU1-deficient cells and that 39 proteins were altered in abundance. Several of those proteins are linked to mitochondrial dysfunction and/or perturbed Ca2+ homeostasis, also impacting on regular cytoskeleton (affecting Spectrin) and Golgi architecture, as well as cellular survival mechanisms. Conclusions: Our findings (i) link dysregulation of mitochondrial Ca2+ uptake with muscle pathology (including perturbed lipid homeostasis and ER-Golgi morphology), (ii) support the concept of a functional interplay of ER-Golgi and mitochondria in lipid homeostasis and (iii) reveal the vulnerability of the cellular proteome as part of the MICU1-related pathophysiology.
dc.description.sponsorship This study was supported by the ‘Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen’, the ‘Regierenden Bürgermeister von Berlin - Senatskanzlei Wissenschaft und Forschung’ and the ‘Bundesministerium für Bildung und Forschung’, also in form of the Leibniz-Research-Cluster (grant number: 031A360E). This work was also supported by a grant of the French Muscular Dystrophy Association (AFM-Téléthon) (#21466) to AR and by an NIH grant (RO1 GM102724) to GH. The research leading to these results has also received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 2012-305121 ‘Integrated European –omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases (NEUROMICS)’. RH is a Wellcome Investigator (109915/Z/15/Z), who receives support from the Medical Research Council (UK) (MR/N025431/1), the European Research Council (309548) and the Newton Fund (MR/N027302/1). HL receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412) and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279)
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Wiley
dc.rights © 2021 Nicolai Kohlschmidt et al. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.other Genètica
dc.subject.other Malalties neuromusculars en el infants
dc.subject.other Proteïnes
dc.subject.other Fenotip
dc.subject.other Fisiologia patològica
dc.title Molecular pathophysiology of human MICU1 deficiency
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1111/nan.12694
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/305121
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/309548
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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