Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling

Logan, Clare V.; Sharpe, Jenny A.; Parry, David A.; Johnson, Colin A.; Roberts, Nicola Y.; Bonthron, David T.; Pysden, Karen A.; Abdelhamed, Zakia A.; Morgan, Joanne E.; Santen, Gijs W.E.; Niks, Erik H.; Den Dunnen, Johan T.; Sewry, Caroline A.; Duchen, Michael R.; Logan, Clare V; Sharpe, Jenny A; Parry, David A; Johnson, Colin A; Roberts, Nicola Y; Bonthron, David T; Pysden, Karen A; Szabadkai, Gy�rgy; Torelli, Silvia; Abdelhamed, Zakia A; Childs, Anne Marie; Morgan, Joanne E; Kriek, Marjolein; Phadke, Rahul; Santen, Gijs W E; Niks, Erik H; Whyte, Tamieka; Munteanu, Iulia; den Dunnen, Johan T; Foley, A. Reghan; Wheway, Gabrielle; Szymanska, Katarzyna; Sewry, Caroline A; Natarajan, Subaashini; Duchen, Michael R; Roper, Helen; Van Der Pol, W. Ludo; Lindhout, Dick; Raffaello, Anna; De Stefani, Diego; Sun, Yu; Ginjaar, Ieke; Hurles, Matthew; Rizzuto, Rosario; Muntoni, Francesco; Sheridan, Eamonn

Abstract

Mitochondrial Ca 2+ uptake has key roles in cell life and death. Physiological Ca 2+ signaling regulates aerobic metabolism, whereas pathological Ca 2+ overload triggers cell death. Mitochondrial Ca 2+ uptake is mediated by the Ca 2+ uniporter complex in the inner mitochondrial membrane, which comprises MCU, a Ca 2+ -selective ion channel, and its regulator, MICU1. Here we report mutations of MICU1 in individuals with a disease phenotype characterized by proximal myopathy, learning difficulties and a progressive extrapyramidal movement disorder. In fibroblasts from subjects with MICU1 mutations, agonist-induced mitochondrial Ca 2+ uptake at low cytosolic Ca 2+ concentrations was increased, and cytosolic Ca 2+ signals were reduced. Although resting mitochondrial membrane potential was unchanged in MICU1-deficient cells, the mitochondrial network was severely fragmented. Whereas the pathophysiology of muscular dystrophy and the core myopathies involves abnormal mitochondrial Ca 2+ handling, the phenotype associated with MICU1 deficiency is caused by a primary defect in mitochondrial Ca 2+ signaling, demonstrating the crucial role of mitochondrial Ca 2+ uptake in humans. © 2014 Nature America, Inc.

Citation

Duchen, M. R., Sewry, C. A., Den Dunnen, J. T., Niks, E. H., Santen, G. W., Morgan, J. E., …Sheridan, E. (2014). Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling. Nature Genetics, 46(2), 188-193. https://doi.org/10.1038/ng.2851

• Journal Article Type: Article
• Acceptance Date: Nov 20, 2013
• Publication Date: Feb 1, 2014
• Deposit Date: Jun 7, 2016
• Journal: Nature Genetics
• Print ISSN: 1061-4036
• Electronic ISSN: 1546-1718
• Publisher: Nature Research
• Peer Reviewed: Peer Reviewed
• Volume: 46
• Issue: 2
• Pages: 188-193
• DOI: https://doi.org/10.1038/ng.2851
• Keywords: genetics research, medical genetics, neuromuscular disease
• Public URL: https://uwe-repository.worktribe.com/output/939149
• Publisher URL: http://dx.doi.org/10.1038/ng.2851