SMDT1 variants impair EMRE-mediated mitochondrial calcium uptake in patients with muscle involvement

Elianne P. Bulthuis, Merel J.W. Adjobo-Hermans, Bastiaan de Potter, Saskia Hoogstraten, Lisanne H.T. Wezendonk, Omar A.Z. Tutakhel, Liesbeth T. Wintjes, Bert van den Heuvel, Peter H.G.M. Willems, Erik Jan Kamsteeg, M. Estela Rubio Gozalbo, Suzanne C.E.H. Sallevelt, Suzanne M. Koudijs, Joost Nicolai, Charlotte I. de Bie, Jessica E. Hoogendijk, Werner J.H. Koopman*, Richard J. Rodenburg

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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 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.
Original languageEnglish
Article number166808
Number of pages14
JournalBiochimica et Biophysica Acta-Molecular Basis of Disease
Volume1869
Issue number8
DOIs
Publication statusPublished - 1 Dec 2023

Keywords

  • Calcium
  • EMRE
  • MCU
  • Mitochondria
  • Muscle involvement
  • SMDT1

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