Molecular pathophysiology of human MICU1 deficiency

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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.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.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.doi http://dx.doi.org/10.1111/nan.12694
• dc.identifier.issn 0305-1846
• dc.identifier.uri http://hdl.handle.net/10230/53447
• dc.language.iso eng
• dc.publisher Wiley
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/305121
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/309548
• 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.accessRights info:eu-repo/semantics/openAccess
• 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.type.version info:eu-repo/semantics/publishedVersion