Please use this identifier to cite or link to this item:
http://doi.org/10.25358/openscience-8795
Authors: | Wolf, Christina Pouya, Alireza Bitar, Sara Pfeiffer, Annika Bueno, Diones Rojas-Charry, Liliana Arndt, Sabine Gomez-Zepeda, David Tenzer, Stefan Dal Bello, Federica Vianello, Caterina Ritz, Sandra Schwirz, Jonas Dobrindt, Kristina Peitz, Michael Hanschmann, Eva-Maria Mencke, Pauline Boussaad, Ibrahim Silies, Marion Brüstle, Oliver Giacomello, Marta Krüger, Rejko Methner, Axel |
Title: | GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton |
Online publication date: | 10-Feb-2023 |
Year of first publication: | 2022 |
Language: | english |
Abstract: | Charcot-Marie-Tooth (CMT) disease 4A is an autosomal-recessive polyneuropathy caused by mutations of ganglioside-induced differentiation-associated protein 1 (GDAP1), a putative glutathione transferase, which affects mitochondrial shape and alters cellular Ca2+ homeostasis. Here, we identify the underlying mechanism. We found that patient-derived motoneurons and GDAP1 knockdown SH-SY5Y cells display two phenotypes: more tubular mitochondria and a metabolism characterized by glutamine dependence and fewer cytosolic lipid droplets. GDAP1 interacts with the actin-depolymerizing protein Cofilin-1 and beta-tubulin in a redox-dependent manner, suggesting a role for actin signaling. Consistently, GDAP1 loss causes less F-actin close to mitochondria, which restricts mitochondrial localization of the fission factor dynamin-related protein 1, instigating tubularity. GDAP1 silencing also disrupts mitochondria-ER contact sites. These changes result in lower mitochondrial Ca2+ levels and inhibition of the pyruvate dehydrogenase complex, explaining the metabolic changes upon GDAP1 loss of function. Together, our findings reconcile GDAP1-associated phenotypes and implicate disrupted actin signaling in CMT4A pathophysiology. |
DDC: | 610 Medizin 610 Medical sciences |
Institution: | Johannes Gutenberg-Universität Mainz |
Department: | FB 04 Medizin |
Place: | Mainz |
ROR: | https://ror.org/023b0x485 |
DOI: | http://doi.org/10.25358/openscience-8795 |
Version: | Published version |
Publication type: | Zeitschriftenaufsatz |
License: | CC BY |
Information on rights of use: | https://creativecommons.org/licenses/by/4.0/ |
Journal: | Communications biology 5 |
Pages or article number: | 541 |
Publisher: | BioMed Central |
Publisher place: | London |
Issue date: | 2022 |
ISSN: | 2399-3642 |
Publisher DOI: | 10.1038/s42003-022-03487-6 |
Appears in collections: | DFG-491381577-G |
Files in This Item:
File | Description | Size | Format | ||
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![]() | gdap1_loss_of_function_inhibi-20230210101611363.pdf | 3.67 MB | Adobe PDF | View/Open |