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

During muscle contraction, increased influx of calcium from the myocyte cytosol into the mitochondrial matrix through the mitochondrial calcium uniporter (MCU) links calcium homeostasis with high ATP provision. The MCU is located at the inner mitochondrial membrane and one of its structural components, the mitochondrial calcium uniporter regulator 1 (MCUR1), promotes its activity. Although MCUR1 function has been studied in cell models, mutations have not yet been associated with human disease. Here, we present a patient with proximal muscle weakness and atrophy, showing histological features of autophagic vacuoles with sarcolemmal features, who carries a homozygous MCUR1 nonsense mutation. To investigate the underlying mechanisms of muscle pathology, we examined patient fibroblasts and quadriceps muscle specimens. MCUR1 deficiency compromised mtCa²⁺ uptake, that had been stimulated both by histamine or rising extracellular calcium exposure. Autophagic flux and histologic markers for autophagy (LAMP2, LCB3) were increased in the patient. However, the MCUR1 mutation did not alter MCU-complex assembly or its subcellular location, nor the resting mitochondrial membrane potential. Our study associates MCUR1 deficiency with mitochondrial dysfunction and autophagic vacuolar myopathy, thereby highlighting the crucial role of mtCa²⁺ uptake in regulating mitochondrial function and expanding the spectrum of mitochondrial disorders in humans.