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