Journal
NEUROBIOLOGY OF DISEASE
Volume 55, Issue -, Pages 140-151Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2013.03.010
Keywords
GDAP1; Charcot-Marie-Tooth disease; Mitochondrial distribution and motility; Endoplasmic reticulum; Calcium homeostasis; Store-operated Ca2+ entry
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Funding
- Spanish Ministry of Science and Innovation [SAF2009-07063, BFU2011-30456-C02-01/BMC]
- Generalitat Valenciana Prometeo Programme [2009/059]
- Comunidad de Madrid [S2010/BMD-2402 MITOLAB-CM]
- Fundacion Ramon Areces
- IRDiRC
- ISCIII [IR11/TREAT-CMT]
- Instituto de Salud Carlos III
- CIBERER
- Comunidad de Madrid
- FPI
- FPU
- Spanish Ministry of Science and Innovation
- INGENIO programme
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GDAP1 is an outer mitochondrial membrane protein that acts as a regulator of mitochondrial dynamics. Mutations of the GDAP1 gene cause Charcot-Marie-Tooth (CMT) neuropathy. We show that GDAP1 interacts with the vesicle-organelle trafficking proteins RAB6B and caytaxin, which suggests that GDAP1 may participate in the mitochondrial movement within the cell. GDAP1 silencing in the SH-SY5Y cell line induces abnormal distribution of the mitochondrial network, reduces the contact between mitochondria and endoplasmic reticulum (ER) and alters the mobilization of mitochondria towards plasma membrane upon depletion of ER-Ca2+ stores. GDAP1 silencing does not affect mitochondrial Ca2+ uptake, ER-Ca2+, or Ca2+ flow from ER to mitochondria, but reduces Ca2+ inflow through store-operated Ca2+ entry (SOCE) following mobilization of ER-Ca2+ and SOCE-driven Ca2+ entry in mitochondria. Our studies suggest that the pathophysiology of GDAP1-related CMT neuropathies may be associated with abnormal distribution and movement of mitochondria throughout cytoskeleton towards the ER and subplasmalemmal microdomains, resulting in a decrease in SOCE activity and impaired SOCE-driven Ca2+ uptake in mitochondria. (c) 2013 Elsevier Inc. All rights reserved.
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