SMDT1variants impair EMRE-mediated mitochondrial calcium uptake in patients with muscle involvement

Abstract

Ionic calcium (Ca2+) is a key messenger in signal transduction and its mitochondrial uptake plays an important role in cell physiology. This uptake is mediated by the mitochondrial Ca2+ uniporter (MCU), which is regulated by EMRE (essential MCU regulator) encoded by the SMDT1 (single-pass membrane protein with aspartate rich tail 1) gene. This work presents the genetic, clinical and cellular characterization of two patients harbouring SMDT1 variants and presenting with muscle problems. Analysis of patient fibroblasts and complementation experiments provide evidence that these variants lead to absence of EMRE protein, induce MCU subcomplex formation and impair mitochondrial Ca2+ uptake. However, the activity of the oxidative phosphorylation enzymes, mitochondrial morphology and membrane potential, as well as routine/ATP-linked respiration were not affected. We hypothesize that the muscle-related symptoms in the patients with SMDT1 variants result from aberrant mitochondrial Ca2+ uptake.

Beyond the matrix: structural and physiological advancements in mitochondrial calcium signaling

“…Although no MCU mutation has ever been identified in humans, a recent preprint by Bulthuis et al [ 71 ] reported two patients with EMRE mutations that lead to a loss of EMRE protein. Muscle breakdown was a common phenotype observed in both patients, who otherwise showed diverse symptoms.…”

Bitter taste receptor (TAS2R) 46 in human skeletal muscle: expression and activity

“…The importance of mitochondria in shaping Ca 2+ -signals has been long known (Rizzuto et al, 2012) and it is also likely that this increased Ca 2+ also alters mitochondrial bioenergetics, although we did not directly investigate it. In skeletal muscle, the importance of mitochondrial Ca 2+ is less characterized than in other cell types but is important to note that mutations of the proteins involved in mitochondrial Ca 2+ -transport have been very recently shown to lead to muscle dysfunction (Bulthuis, et al, 2022) providing evidence that this mechanism is highly relevant.…”