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.

GDAP1 mutations effect Charcot-Marie-Tooth disease 4A by inhibiting the pyruvate dehydrogenase complex and restricting mitochondrial localization of dynamin-related protein 1 through alterations of the actin cytoskeleton.

Details

Title
GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton
Author
Wolf, Christina 1 ; Pouya, Alireza 1   VIAFID ORCID Logo  ; Bitar, Sara 1 ; Pfeiffer, Annika 1   VIAFID ORCID Logo  ; Bueno, Diones 1   VIAFID ORCID Logo  ; Rojas-Charry, Liliana 1 ; Arndt, Sabine 2   VIAFID ORCID Logo  ; Gomez-Zepeda, David 2 ; Tenzer, Stefan 2   VIAFID ORCID Logo  ; Bello, Federica Dal 3 ; Vianello, Caterina 3   VIAFID ORCID Logo  ; Ritz, Sandra 4 ; Schwirz, Jonas 4 ; Dobrindt, Kristina 5 ; Peitz, Michael 6   VIAFID ORCID Logo  ; Hanschmann, Eva-Maria 7 ; Mencke, Pauline 8 ; Boussaad, Ibrahim 9   VIAFID ORCID Logo  ; Silies, Marion 10   VIAFID ORCID Logo  ; Brüstle, Oliver 5 ; Giacomello, Marta 11   VIAFID ORCID Logo  ; Krüger, Rejko 12 ; Methner, Axel 1   VIAFID ORCID Logo 

 University Medical Center Mainz, Institute of Molecular Medicine, Mainz, Germany (GRID:grid.410607.4) 
 University Medical Center Mainz, Institute for Immunology, Mainz, Germany (GRID:grid.410607.4) 
 University Medical Center Mainz, Institute of Molecular Medicine, Mainz, Germany (GRID:grid.410607.4); University of Padova, Department of Biology, Padova, Italy (GRID:grid.5608.b) (ISNI:0000 0004 1757 3470); University of Padova, Department of Biomedical Sciences, Padova, Italy (GRID:grid.5608.b) (ISNI:0000 0004 1757 3470) 
 Institute of Molecular Biology (IMB) gGmbH, Mainz, Germany (GRID:grid.424631.6) (ISNI:0000 0004 1794 1771) 
 University of Bonn Medical Faculty and University Hospital Bonn, Institute of Reconstructive Neurobiology, Bonn, Germany (GRID:grid.15090.3d) (ISNI:0000 0000 8786 803X) 
 University of Bonn Medical Faculty and University Hospital Bonn, Institute of Reconstructive Neurobiology, Bonn, Germany (GRID:grid.15090.3d) (ISNI:0000 0000 8786 803X); University of Bonn School of Medicine, Cell Programming Core Facility, Bonn, Germany (GRID:grid.10388.32) (ISNI:0000 0001 2240 3300) 
 Heinrich-Heine University, Department of Neurology, Medical Faculty, Düsseldorf, Germany (GRID:grid.411327.2) (ISNI:0000 0001 2176 9917) 
 University of Luxembourg, Translational Neuroscience, Luxembourg Centre for Systems Biomedicine (LCSB), Belvaux, Luxembourg (GRID:grid.16008.3f) (ISNI:0000 0001 2295 9843) 
 University of Luxembourg, Translational Neuroscience, Luxembourg Centre for Systems Biomedicine (LCSB), Belvaux, Luxembourg (GRID:grid.16008.3f) (ISNI:0000 0001 2295 9843); University of Luxembourg and Luxembourg Institute of Health (LIH), Disease Modeling and Screening Platform (DMSP), Luxembourg Centre of Systems Biomedicine (Biomedicine), Belvaux, Luxembourg (GRID:grid.451012.3) (ISNI:0000 0004 0621 531X) 
10  Johannes Gutenberg-University Mainz, Institute of Development Biology and Neurobiology, Mainz, Germany (GRID:grid.5802.f) (ISNI:0000 0001 1941 7111) 
11  University of Padova, Department of Biology, Padova, Italy (GRID:grid.5608.b) (ISNI:0000 0004 1757 3470); University of Padova, Department of Biomedical Sciences, Padova, Italy (GRID:grid.5608.b) (ISNI:0000 0004 1757 3470) 
12  University of Luxembourg, Translational Neuroscience, Luxembourg Centre for Systems Biomedicine (LCSB), Belvaux, Luxembourg (GRID:grid.16008.3f) (ISNI:0000 0001 2295 9843); Transversal Translational Medicine, Luxembourg Institute of Health (LIH), Strassen, Luxembourg (GRID:grid.451012.3) (ISNI:0000 0004 0621 531X) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
23993642
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2672843774
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.