title: CMT-linked loss-of-function mutations in GDAP1 impair store-operated Ca2+entry-stimulated respiration.
abstract: GDAP1 is an outer mitochondrial membrane protein involved in Charcot-Marie-Tooth (CMT) disease. Lack of GDAP1 gives rise to altered mitochondrial networks and endoplasmic reticulum (ER)-mitochondrial interactions resulting in a decreased ER-Ca2+levels along with a defect on store-operated calcium entry (SOCE) related to a misallocation of mitochondria to subplasmalemmal sites. The defect on SOCE is mimicked by MCU silencing or mitochondrial depolarization, which prevent mitochondrial calcium uptake. Ca2+release from de ER and Ca2+inflow through SOCE in neuroblastoma cells result in a Ca2+-dependent upregulation of respiration which is blunted in GDAP1 silenced cells. Reduced SOCE in cells with CMT recessive missense mutations in the α-loop of GDAP1, but not dominant mutations, was associated with smaller SOCE-stimulated respiration. These cases of GDAP1 deficiency also resulted in a decreased ER-Ca2+levels which may have pathological implications. The results suggest that CMT neurons may be under energetic constraints upon stimulation by Ca2+mobilization agonists and point to a potential role of perturbed mitochondria-ER interaction related to energy metabolism in forms of CMT caused by some of the recessive or null mutations of GDAP1.
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, 28049, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, 28029, Spain.|Instituto de Investigación Sanitaria Fundación Jiménez Díaz, IIS-FJD, Madrid, 28040, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: González-Sánchez
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, 28029, Spain.|Program in Rare and Genetic Diseases and IBV/CSIC Associated Unit, Centro de Investigación Príncipe Felipe, Valencia, 46012, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Pla-Martín
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, 28049, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, 28029, Spain.|Instituto de Investigación Sanitaria Fundación Jiménez Díaz, IIS-FJD, Madrid, 28040, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Martínez-Valero
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, 28049, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, 28029, Spain.|Instituto de Investigación Sanitaria Fundación Jiménez Díaz, IIS-FJD, Madrid, 28040, Spain.
authors.forename: Carlos B
authors.initials: CB
authors.lastname: Rueda
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, 28029, Spain.|Program in Rare and Genetic Diseases and IBV/CSIC Associated Unit, Centro de Investigación Príncipe Felipe, Valencia, 46012, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Calpena
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, 28029, Spain.|Instituto de Investigación Sanitaria Fundación Jiménez Díaz, IIS-FJD, Madrid, 28040, Spain.|Facultad de Ciencias Ambientales y Bioquímica, Universidad de Castilla la Mancha, Toledo, 45071, Spain.
authors.forename: Araceli
authors.initials: A
authors.lastname: Del Arco
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, 28029, Spain.|Program in Rare and Genetic Diseases and IBV/CSIC Associated Unit, Centro de Investigación Príncipe Felipe, Valencia, 46012, Spain.|Institut de Recerca Sant Joan de Déu and Hospital Sant Joan de Déu, Barcelona 08950, Spain.|Pediatrics Division, University of Barcelona School of Medicine, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Palau
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, 28049, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, 28029, Spain.|Instituto de Investigación Sanitaria Fundación Jiménez Díaz, IIS-FJD, Madrid, 28040, Spain.
authors.forename: Jorgina
authors.initials: J
authors.lastname: Satrústegui
mesh_terms: D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009840:Oligomycins / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D015220:Calcium Channels; C118663:GDAP protein; D009419:Nerve Tissue Proteins; D009840:Oligomycins; D034741:RNA, Small Interfering; C034703:mitochondrial calcium uniporter; D002118:Calcium