Biallelic MCUR1 nonsense mutation associated with vacuolar myopathy and altered mitochondrial calcium signaling

Abstract During muscle contraction, increased influx of mitochondrial calcium (mtCa²⁺) from the myocyte cytosol through the mitochondrial calcium uniporter (MCU) couples calcium homeostasis with high ATP provision. The mitochondrial calcium uniporter regulator 1 (MCUR1) is an integral membrane protein that promotes MCU activity. Although its function has been studied in cell models, mutations in MCUR1 have not yet been associated with human disease. Here, we present a case study of a patient exhibiting proximal muscle weakness and atrophy, who carries a novel homozygous loss-of-function mutation in MCUR1. To investigate the underlying mechanisms of muscle pathology, we examined patient fibroblasts and quadriceps muscle specimens. MCUR1 deficiency compromised mitochondrial Ca²⁺ uptake upon histamine exposure, but did not alter resting mitochondrial membrane potential or MCU protein complex assembly or subcellular location. Consequently, ATP production and oxygen consumption were reduced, and mitochondrial biogenesis was disturbed in muscle, with histological features of autophagic vacuoles with sarcolemmal features. Our study associates MCUR1 deficiency with mitochondrial dysfunction and autophagic vacuolar myopathy, thereby highlighting the crucial role of mitochondrial Ca²⁺ uptake in regulating mitochondrial function and expanding the spectrum of mitochondrial disorders in humans. Graphical abstract