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

被引：2

作者：

Bulthuis, Elianne P. ^{[1
]}

Adjobo-Hermans, Merel J. W. ^{[1
]}

de Potter, Bastiaan ^{[1
]}

Hoogstraten, Saskia ^{[1
,2
]}

Wezendonk, Lisanne H. T. ^{[1
]}

Tutakhel, Omar A. Z. ^{[3
]}

Wintjes, Liesbeth T. ^{[3
]}

van den Heuvel, Bert ^{[3
]}

Willems, Peter H. G. M. ^{[1
]}

Kamsteeg, Erik-Jan ^{[4
]}

Gozalbo, M. Estela Rubio ^{[5
,6
]}

Sallevelt, Suzanne C. E. H. ^{[6
]}

Koudijs, Suzanne M. ^{[7
]}

Nicolai, Joost ^{[7
]}

de Bie, Charlotte I. ^{[8
]}

Hoogendijk, Jessica E. ^{[9
]}

Koopman, Werner J. H. ^{[2
,10
,11
,12
]}

Rodenburg, Richard J. ^{[10
,11
,13
]}

机构：

[1] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Dept Biochem 286, NL-6525 GA Nijmegen, Netherlands

[2] Wageningen Univ & Res, Human & Anim Physiol, NL-6700 AH Wageningen, Netherlands

[3] Radboud Univ Nijmegen, Dept Lab Med, Translat Metab Lab, Med Ctr, NL-6525 GA Nijmegen, Netherlands

[4] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands

[5] Maastricht Univ, Med Ctr, Dept Pediat, NL-6229 HX Maastricht, Netherlands

[6] Maastricht Univ, Med Ctr, Dept Clin Genet, NL-6229 HX Maastricht, Netherlands

[7] Maastricht Univ, Med Ctr, Dept Neurol, NL-6229 HX Maastricht, Netherlands

[8] Univ Med Ctr Utrecht, Dept Genet, NL-3508 AB Utrecht, Netherlands

[9] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, NL-3584 CG Utrecht, Netherlands

[10] Radboud Univ Nijmegen, Amalia Childrens Hosp, Radboud Inst Mol Life Sci, Radboud Ctr Mitochondrial Med,Med Ctr,Dept Pediat, NL-6500 HB Nijmegen, Netherlands

[11] Radboud Univ Nijmegen, Dept Pediat, Med Ctr, NL-6500 HB Nijmegen, Netherlands

[12] Radboud Univ Nijmegen, Med Ctr Radboudumc, Radboud Inst Mitochondrial Med RCMM, Radboud Ctr Mol Life Sci RIMLS,Amalia Childrens Ho, POB 9101, NL-6500 HB Nijmegen, Netherlands

[13] Radboud Univ Nijmegen, Med Ctr Radboudumc, Radboud Inst Mitochondrial Med RCMM, Radboud Ctr Mol Life Sci RIMLS,Amalia Childrens Ho, POB 9101, NL-6500 HB Nijmegen, Netherlands

来源：

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE | 2023年 / 1869卷 / 08期

关键词：

EMRE; SMDT1; MCU; Mitochondria; Calcium; Muscle involvement; ATP PRODUCTION; CA2+ UPTAKE; ENDOPLASMIC-RETICULUM; ESSENTIAL COMPONENT; MICE LACKING; RAT-HEART; UNIPORTER; MEMBRANE; MCU; DEHYDROGENASE;

D O I：

10.1016/j.bbadis.2023.166808

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：14

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