Molecular pathophysiology of human MICU1 deficiency.

Autor: Kohlschmidt N; Institute of Clinical Genetics and Tumour Genetics, Bonn, Germany., Elbracht M; Institute of Human Genetics, RWTH Aachen University Hospital, Aachen, Germany., Czech A; Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V, Dortmund, Germany., Häusler M; Division of Neuropediatrics and Social Pediatrics, Department of Pediatrics, RWTH Aachen University Hospital, Aachen, Germany., Phan V; Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V, Dortmund, Germany., Töpf A; Institute of Genetic Medicine, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK., Huang KT; MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA., Bartok A; MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA., Eggermann K; Institute of Human Genetics, RWTH Aachen University Hospital, Aachen, Germany., Zippel S; Centre for Social Pediatrics Mechernich, Mechernich, Germany., Eggermann T; Institute of Human Genetics, RWTH Aachen University Hospital, Aachen, Germany., Freier E; Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V, Dortmund, Germany., Groß C; Institute of Clinical Genetics and Tumour Genetics, Bonn, Germany., Lochmüller H; Department of Neuropediatrics and Muscle Disorders, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.; Centro Nacional de Análisis Genómico, Center for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain.; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.; Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada., Horvath R; Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK., Hajnóczky G; MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA., Weis J; Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany., Roos A; Department of Neuropediatrics, Centre for Neuromuscular Disorders in Children, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Jazyk: angličtina
Zdroj: Neuropathology and applied neurobiology [Neuropathol Appl Neurobiol] 2021 Oct; Vol. 47 (6), pp. 840-855. Date of Electronic Publication: 2021 Feb 22.
DOI: 10.1111/nan.12694
Abstrakt: Aims: MICU1 encodes the gatekeeper of the mitochondrial Ca 2+ 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 Ca 2+ 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 Ca 2+ transport and proteomic studies on lymphoblastoid cells revealed that the [Ca 2+ ] threshold and the cooperative activation of mitochondrial Ca 2+ 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 Ca 2+ 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 Ca 2+ 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.
(© 2021 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)
Databáze: MEDLINE
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