TY - JOUR
T1 - SMDT1 variants impair EMRE-mediated mitochondrial calcium uptake in patients with muscle involvement
AU - Bulthuis, Elianne P.
AU - Adjobo-Hermans, Merel J.W.
AU - de Potter, Bastiaan
AU - Hoogstraten, Saskia
AU - Wezendonk, Lisanne H.T.
AU - Tutakhel, Omar A.Z.
AU - Wintjes, Liesbeth T.
AU - van den Heuvel, Bert
AU - Willems, Peter H.G.M.
AU - Kamsteeg, Erik Jan
AU - Gozalbo, M. Estela Rubio
AU - Sallevelt, Suzanne C.E.H.
AU - Koudijs, Suzanne M.
AU - Nicolai, Joost
AU - de Bie, Charlotte I.
AU - Hoogendijk, Jessica E.
AU - Koopman, Werner J.H.
AU - Rodenburg, Richard J.
N1 - Funding Information:
Werner J.H. Koopman was supported by a junior researcher grant (Elianne P. Bulthuis; Radboudmc , Nijmegen, The Netherlands), the Next Level Animal Sciences (NLAS) initiative (“Data and Models”) of the Wageningen University (Wageningen, The Netherlands) and by Principal Investigator (PI) support funding ( Radboudumc ). These organizations were not involved in the data analysis and interpretation, writing of the manuscript and in the decision to submit the manuscript for publication.
Funding Information:
We thank Jozef Hertecant (Department of Pediatrics, Tawam Hospital, United Arab Emirates) for clinical diagnosis and care of patient 3 (P3-MICU1), Dr. Laszlo Groh (Dept. of Internal Medicine, Radboudumc) and Els van de Westerlo (Dept. of Biochemistry, Radboudumc) for their practical assistance with Seahorse and Western blot experiments, the colleagues of the mitochondrial diagnostic group (muscle lab, cell culture lab and DNA lab) of the Translational Metabolic Laboratory at the Radboudumc for excellent technical assistance, the Genome Technology Centre at the Radboudumc and BGI Copenhagen for technical support of the exome sequencing, Dr. Sander Groffen (Department of Human Genetics, Amsterdam UMC, The Netherlands) for assisting in WES data interpretation, and Khondrion B.V. (Nijmegen, The Netherlands) for providing access to their microscopy hardware. Werner J.H. Koopman was supported by a junior researcher grant (Elianne P. Bulthuis; Radboudmc, Nijmegen, The Netherlands), the Next Level Animal Sciences (NLAS) initiative (“Data and Models”) of the Wageningen University (Wageningen, The Netherlands) and by Principal Investigator (PI) support funding (Radboudumc). These organizations were not involved in the data analysis and interpretation, writing of the manuscript and in the decision to submit the manuscript for publication. An earlier version of this manuscript ([89]) is available on the preprint server BioRxiv, DOI: https://doi.org/10.1101/2022.10.31.514480
Publisher Copyright:
© 2023 The Author(s)
PY - 2023/12/1
Y1 - 2023/12/1
N2 - 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 demonstrated that these variants lead to absence of EMRE protein, induce MCU subcomplex formation and impair mitochondrial Ca2+ uptake. However, the activity of 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 SMDT1 patients result from aberrant mitochondrial Ca2+ uptake.
AB - 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 demonstrated that these variants lead to absence of EMRE protein, induce MCU subcomplex formation and impair mitochondrial Ca2+ uptake. However, the activity of 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 SMDT1 patients result from aberrant mitochondrial Ca2+ uptake.
KW - Calcium
KW - EMRE
KW - MCU
KW - Mitochondria
KW - Muscle involvement
KW - SMDT1
U2 - 10.1016/j.bbadis.2023.166808
DO - 10.1016/j.bbadis.2023.166808
M3 - Article
C2 - 37454773
SN - 0925-4439
VL - 1869
JO - Biochimica et Biophysica Acta-Molecular Basis of Disease
JF - Biochimica et Biophysica Acta-Molecular Basis of Disease
IS - 8
M1 - 166808
ER -