title: Silencing of the Charcot-Marie-Tooth disease-associated gene GDAP1 induces abnormal mitochondrial distribution and affects Ca2+ homeostasis by reducing store-operated Ca2+ entry.
abstract: 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-Ca(2+) stores. GDAP1 silencing does not affect mitochondrial Ca(2+) uptake, ER-Ca(2+), or Ca(2+) flow from ER to mitochondria, but reduces Ca(2+) inflow through store-operated Ca(2+) entry (SOCE) following mobilization of ER-Ca(2+) and SOCE-driven Ca(2+) 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 Ca(2+) uptake in mitochondria.
authors.affiliation: Laboratory of Genetics and Molecular Medicine, Instituto de Biomedicina de Valencia, CSIC, Valencia, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Pla-Martín
authors.forename: Carlos B
authors.initials: CB
authors.lastname: Rueda
authors.forename: Anna
authors.initials: A
authors.lastname: Estela
authors.forename: Maribel
authors.initials: M
authors.lastname: Sánchez-Piris
authors.forename: Paloma
authors.initials: P
authors.lastname: González-Sánchez
authors.forename: Javier
authors.initials: J
authors.lastname: Traba
authors.forename: Sergio
authors.initials: S
authors.lastname: de la Fuente
authors.forename: Luca
authors.initials: L
authors.lastname: Scorrano
authors.forename: Jaime
authors.initials: J
authors.lastname: Renau-Piqueras
authors.forename: Javier
authors.initials: J
authors.lastname: Alvarez
authors.forename: Jorgina
authors.initials: J
authors.lastname: Satrústegui
authors.forename: Francesc
authors.initials: F
authors.lastname: Palau
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics*; D002461:Cell Line, Transformed; D002614:Chelating Agents / Q000494:pharmacology; D020756:Coatomer Protein / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004533:Egtazic Acid / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D034622:RNA Interference / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D014162:Transfection; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: D002614:Chelating Agents; D020756:Coatomer Protein; D004791:Enzyme Inhibitors; C118663:GDAP protein; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; C084008:TOMM20 protein, human; C053387:endoplasmin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D004533:Egtazic Acid; D000255:Adenosine Triphosphate; C417211:RAB6C protein, human; D020691:rab GTP-Binding Proteins; D002118:Calcium