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

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^1,2, 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 dystrophy³ and the core myopathies⁴ 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.