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. 2023 Dec;1869(8):166808.
doi: 10.1016/j.bbadis.2023.166808. Epub 2023 Jul 16.

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

Elianne P Bulthuis  1 , Merel J W Adjobo-Hermans  1 , Bastiaan de Potter  1 , Saskia Hoogstraten  2 , Lisanne H T Wezendonk  1 , Omar A Z Tutakhel  3 , Liesbeth T Wintjes  3 , Bert van den Heuvel  3 , Peter H G M Willems  1 , Erik-Jan Kamsteeg  4 , M Estela Rubio Gozalbo  5 , Suzanne C E H Sallevelt  6 , Suzanne M Koudijs  7 , Joost Nicolai  7 , Charlotte I de Bie  8 , Jessica E Hoogendijk  9 , Werner J H Koopman  10 , Richard J Rodenburg  11
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Free article

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

Elianne P Bulthuis et al. Biochim Biophys Acta Mol Basis Dis. 2023 Dec.
Free article

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.

Keywords: Calcium; EMRE; MCU; Mitochondria; Muscle involvement; SMDT1.

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Conflict of interest statement

Declaration of competing interest WJHK is a scientific advisor of Khondrion B.V. (Nijmegen, The Netherlands). This company was not involved in the data analysis and interpretation, writing of the manuscript, and in the decision to submit the manuscript for publication.

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