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

doi:10.1016/j.bbadis.2023.166808

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 journal › Article › Academic › peer-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 language	English
Article number	166808
Number of pages	14
Journal	Biochimica et Biophysica Acta. Molecular Basis of Disease
Volume	1869
Issue number	8
DOIs	https://doi.org/10.1016/j.bbadis.2023.166808
Publication status	Published - Dec 2023

Keywords

Calcium Channels/genetics
Calcium/metabolism
Humans
Ion Transport
Mitochondria/genetics
Muscles/metabolism

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Bulthuis, E. P., Adjobo-Hermans, M. J. W., de Potter, B., Hoogstraten, S., Wezendonk, L. H. T., Tutakhel, O. A. Z., Wintjes, L. T., van den Heuvel, B., Willems, P. H. G. M., Kamsteeg, E.-J., Gozalbo, M. E. R., Sallevelt, S. C. E. H., Koudijs, S. M., Nicolai, J., de Bie, C. I., Hoogendijk, J. E., Koopman, W. J. H., & Rodenburg, R. J. (2023). SMDT1 variants impair EMRE-mediated mitochondrial calcium uptake in patients with muscle involvement. Biochimica et Biophysica Acta. Molecular Basis of Disease, 1869(8), Article 166808. https://doi.org/10.1016/j.bbadis.2023.166808

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title = "SMDT1 variants 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 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 Channels/genetics, Calcium/metabolism, Humans, Ion Transport, Mitochondria/genetics, Muscles/metabolism",

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

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = dec,

doi = "10.1016/j.bbadis.2023.166808",

language = "English",

volume = "1869",

journal = "Biochimica et Biophysica Acta. Molecular Basis of Disease",

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Bulthuis, EP, Adjobo-Hermans, MJW, de Potter, B, Hoogstraten, S, Wezendonk, LHT, Tutakhel, OAZ, Wintjes, LT, van den Heuvel, B, Willems, PHGM, Kamsteeg, E-J, Gozalbo, MER, Sallevelt, SCEH, Koudijs, SM, Nicolai, J, de Bie, CI, Hoogendijk, JE, Koopman, WJH & Rodenburg, RJ 2023, 'SMDT1 variants impair EMRE-mediated mitochondrial calcium uptake in patients with muscle involvement', Biochimica et Biophysica Acta. Molecular Basis of Disease, vol. 1869, no. 8, 166808. https://doi.org/10.1016/j.bbadis.2023.166808

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

PY - 2023/12

Y1 - 2023/12

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 Channels/genetics

KW - Calcium/metabolism

KW - Humans

KW - Ion Transport

KW - Mitochondria/genetics

KW - Muscles/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85166972580&partnerID=8YFLogxK

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 -

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

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