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

Logan, C.V., Szabadkai, G., Sharpe, J.A., Parry, D.A., Torelli, S., Childs, A.-M., Kriek, M., Phadke, R., Johnson, C.A., Roberts, N.Y., Bonthron, D.T., Pysden, K.A., Whyte, T., Munteanu, I., Foley, A.R., Wheway, G., Szymanska, K., Natarajan, S., Abdelhamed, Z.A., Morgan, J.E., Roper, H., Santen, G.W.E., Niks, E.H., van der Pol, W.L., Lindhout, D., Raffaello, A., De Stefani, D., den Dunnen, J.T., Sun, Y., Ginjaar, I., Sewry, C.A., Hurles, M., Rizzuto, R., Duchen, M.R., Muntoni, F. and Sheridan, E. , UK10K Consortium (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. (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.

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Contributors

Author: G. Wheway

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