SMDT1 variants impair EMRE-mediated mitochondrial calcium uptake in patients with muscle involvement
Publication date
2023-12
Authors
Bulthuis, Elianne P
Adjobo-Hermans, Merel J W
de Potter, Bastiaan
Hoogstraten, Saskia
Wezendonk, Lisanne H T
Tutakhel, Omar A Z
Wintjes, Liesbeth T
van den Heuvel, Bert
Willems, Peter H G M
Kamsteeg, Erik-Jan
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Supervisors
Document Type
Article
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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, Journal Article, Research Support, Non-U.S. Gov't
Citation
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, vol. 1869, no. 8, 166808. https://doi.org/10.1016/j.bbadis.2023.166808