期刊
SCIENTIFIC REPORTS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep42993
关键词
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资金
- Spanish Ministry of Science and Innovation [SAF2012-32425, BFU2011-30456-C02-01/BMC, SAF2014-56929]
- Generalitat Valenciana Programme [PROMETEOII/2014/029]
- Comunidad de Madrid [S2010/BMD-2402]
- Fundacion Ramon Areces
- IRDiRC
- ISCIII [IR11/TREAT-CMT]
- CIBERER
- INGENIO programme
- Universidad Autonoma de Madrid
- CIBERER [IR11/TREAT-CMT]
- FPU fellowships from the Ministerio de Economia y Competitividad
- FPI fellowship from the Ministerio de Economia y Competitividad
- Instituto de Salud Carlos III
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.
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