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

Biochim Biophys Acta Mol Basis Dis. 2023 Dec;1869(8):166808. doi: 10.1016/j.bbadis.2023.166808. Epub 2023 Jul 16.

Authors

Elianne P Bulthuis¹, Merel J W Adjobo-Hermans¹, Bastiaan de Potter¹, Saskia Hoogstraten², Lisanne H T Wezendonk¹, Omar A Z Tutakhel³, Liesbeth T Wintjes³, Bert van den Heuvel³, Peter H G M Willems¹, Erik-Jan Kamsteeg⁴, M Estela Rubio Gozalbo⁵, Suzanne C E H Sallevelt⁶, Suzanne M Koudijs⁷, Joost Nicolai⁷, Charlotte I de Bie⁸, Jessica E Hoogendijk⁹, Werner J H Koopman¹⁰, Richard J Rodenburg¹¹

Affiliations

¹ Department of Biochemistry (286), Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
² Department of Biochemistry (286), Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Human and Animal Physiology, Wageningen University & Research, 6700 AH Wageningen, the Netherlands.
³ Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
⁴ Department of Human Genetics, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
⁵ Department of Pediatrics, Maastricht University Medical Centre, 6229 HX Maastricht, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Centre, 6229 HX Maastricht, the Netherlands.
⁶ Department of Clinical Genetics, Maastricht University Medical Centre, 6229 HX Maastricht, the Netherlands.
⁷ Department of Neurology, Maastricht University Medical Centre, 6229 HX Maastricht, the Netherlands.
⁸ Department of Genetics, University Medical Centre Utrecht, 3508 AB Utrecht, the Netherlands.
⁹ Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, 3584 CG Utrecht, the Netherlands.
¹⁰ Human and Animal Physiology, Wageningen University & Research, 6700 AH Wageningen, the Netherlands; Department of Pediatrics, Amalia Children's Hospital, Radboud Center for Mitochondrial Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address: Werner.Koopman@radboudumc.nl.
¹¹ Department of Pediatrics, Amalia Children's Hospital, Radboud Center for Mitochondrial Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address: Richard.Rodenburg@radboudumc.nl.

PMID: 37454773
DOI: 10.1016/j.bbadis.2023.166808

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Calcium
Calcium Channels
SMDT1 protein, human