Please use this identifier to cite or link to this item:
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
Version: Published version
Publication type: Zeitschriftenaufsatz
License: CC BY
Information on rights of use:
Journal: Communications biology
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 SizeFormat
gdap1_loss_of_function_inhibi-20230210101611363.pdf3.67 MBAdobe PDFView/Open