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

CV Logan, G Szabadkai, JA Sharpe, DA Parry… - Nature …, 2014 - nature.com
CV Logan, G Szabadkai, JA Sharpe, DA Parry, S Torelli, AM Childs, M Kriek, R Phadke…
Nature genetics, 2014nature.com
Mitochondrial Ca2+ uptake has key roles in cell life and death. Physiological Ca2+ signaling
regulates aerobic metabolism, whereas pathological Ca2+ overload triggers cell death.
Mitochondrial Ca2+ uptake is mediated by the Ca2+ uniporter complex in the inner
mitochondrial membrane,, which comprises MCU, a Ca2+-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 …
Abstract
Mitochondrial Ca2+ uptake has key roles in cell life and death. Physiological Ca2+ signaling regulates aerobic metabolism, whereas pathological Ca2+ overload triggers cell death. Mitochondrial Ca2+ uptake is mediated by the Ca2+ uniporter complex in the inner mitochondrial membrane,, which comprises MCU, a Ca2+-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 Ca2+ uptake at low cytosolic Ca2+ concentrations was increased, and cytosolic Ca2+ 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 Ca2+ handling, the phenotype associated with MICU1 deficiency is caused by a primary defect in mitochondrial Ca2+ signaling, demonstrating the crucial role of mitochondrial Ca2+ uptake in humans.
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