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

  • Nat Genet. 2014 Feb;46(2):188-93. doi: 10.1038/ng.2851.
Clare V Logan ,  György Szabadkai ,  Jenny A Sharpe ,  David A Parry ,  Silvia Torelli ,  Anne-Marie Childs ,  Marjolein Kriek ,  Rahul Phadke ,  Colin A Johnson ,  Nicola Y Roberts ,  David T Bonthron ,  Karen A Pysden ,  Tamieka Whyte ,  Iulia Munteanu ,  A Reghan Foley ,  Gabrielle Wheway ,  Katarzyna Szymanska ,  Subaashini Natarajan ,  Zakia A Abdelhamed ,  Joanne E Morgan ,  Helen Roper ,  Gijs W E Santen ,  Erik H Niks ,  W Ludo van der Pol ,  Dick Lindhout ,  Anna Raffaello ,  Diego De Stefani ,  Johan T den Dunnen ,  Yu Sun ,  Ieke Ginjaar ,  Caroline A Sewry ,  Matthew Hurles ,  Rosario Rizzuto ,  UK10K Consortium ,  Michael R Duchen ,  Francesco Muntoni ,  Eamonn Sheridan
PMID: 24336167 DOI: 10.1038/ng.2851
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.