Universität zu Köln

Gonzalez-Sanchez, Paloma, Pla-Martin, David, Martinez-Valero, Paula, Rueda, Carlos B., Calpena, Eduardo ORCID: 0000-0001-6399-6528, del Arco, Araceli, Palau, Francesc ORCID: 0000-0002-8635-5421 and Satrustegui, Jorgina (2017). CMT-linked loss-of-function mutations in GDAP1 impair store-operated Ca2+ entry-stimulated respiration. Sci Rep, 7. LONDON: NATURE PUBLISHING GROUP. ISSN 2045-2322

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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 a-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Gonzalez-Sanchez, Paloma UNSPECIFIED UNSPECIFIED UNSPECIFIED Pla-Martin, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Martinez-Valero, Paula UNSPECIFIED UNSPECIFIED UNSPECIFIED Rueda, Carlos B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Calpena, Eduardo UNSPECIFIED orcid.org/0000-0001-6399-6528 UNSPECIFIED del Arco, Araceli UNSPECIFIED UNSPECIFIED UNSPECIFIED Palau, Francesc UNSPECIFIED orcid.org/0000-0002-8635-5421 UNSPECIFIED Satrustegui, Jorgina UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-239526
DOI:	10.1038/srep42993
Journal or Publication Title:	Sci Rep
Volume:	7
Date:	2017
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2045-2322
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CHARCOT-MARIE-TOOTH; MITOCHONDRIAL CALCIUM UNIPORTER; DIFFERENTIATION-ASSOCIATED PROTEIN-1; FOUNDER MUTATION; 4A DISEASE; GENE; NEURONS; IDENTIFICATION; EXCITOTOXICITY; BIOENERGETICS Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23952