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

Logan, Clare V and Szabadkai, György and Sharpe, Jenny A and Parry, David A and Torelli, Silvia and Childs, Anne-Marie and Kriek, Marjolein and Phadke, Rahul and Johnson, Colin A and Roberts, Nicola Y and Bonthron, David T and Pysden, Karen A and Whyte, Tamieka and Munteanu, Iulia and Foley, A Reghan and Wheway, Gabrielle and Szymanska, Katarzyna and Natarajan, Subaashini and Abdelhamed, Zakia A and Morgan, Joanne E and Roper, Helen and Santen, Gijs W E and Niks, Erik H and van der Pol, W Ludo and Lindhout, Dick and Raffaello, Anna and De Stefani, Diego and den Dunnen, Johan T and Sun, Yu and Ginjaar, Ieke and Sewry, Caroline A and Hurles, Matthew and Rizzuto, Rosario and Duchen, Michael R and Muntoni, Francesco and Sheridan, Eamonn (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). pp. 188-93. ISSN 1546-1718.

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Official URL: http://www.nature.com/ng/journal/v46/n2/full/ng.28...

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.

Item Type: Article
Subjects: QC-QM General sciences
Divisions: Womens and Childrens > Paediatrics
Related URLs:
Depositing User: Sophie Rollason
Date Deposited: 11 Jun 2014 13:41
Last Modified: 11 Jun 2014 13:41
URI: http://www.repository.heartofengland.nhs.uk/id/eprint/244

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