Reference : GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by a...
E-prints/Working papers : Already available on another site
Life sciences : Biochemistry, biophysics & molecular biology
Systems Biomedicine
http://hdl.handle.net/10993/50307
GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton 2021.03.04.433895
English
Wolf, Christina [University Medical Center Mainz > Institute of Molecular Medicine, Institute for Immunology]
Pouya, Alireza [University Medical Center Mainz > Institute of Molecular Medicine, Institute for Immunology]
Bitar, Sara [University Medical Center Mainz > Institute of Molecular Medicine, Institute for Immunology]
Pfeiffer, Annika [> >]
Bueno, Diones [> >]
Arndt, Sabine [> >]
Tenzer, Stefan [> >]
Dal Bello, Federica [> >]
Vianello, Caterina [> >]
Ritz, Sandra [> >]
Schwirz, Jonas [> >]
Dobrindt, Kristina [> >]
Peitz, Michael [> >]
Hanschmann, Eva-Maria [> >]
Boussaad, Ibrahim mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience]
Brüstle, Oliver [> >]
Giacomello, Marta [> >]
Krüger, Rejko mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience]
Methner, Axel [> >]
2021
Cold Spring Harbor Laboratory
No
[en] GDAP1 ; mitochondria ; cytoskeleton
[en] 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 in a redoxdependent 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. Changes in the actin cytoskeleton also disrupt mitochondria-ER contact sites. This results in lower mitochondrial Ca2+ levels and inhibition of the pyruvate dehydrogenase complex, explaining the metabolic changes upon GDAP1 loss of function. Together, these findings reconcile GDAP1-associated phenotypes and implicate disrupted actin signaling in CMT4A pathophysiology.
Researchers ; Professionals
http://hdl.handle.net/10993/50307
10.1101/2021.03.04.433895
https://www.biorxiv.org/content/early/2021/03/05/2021.03.04.433895
OA
https://www.biorxiv.org/content/10.1101/2021.03.04.433895v1
FnR ; FNR11264123 > Rejko Krüger > NCER-PD > Ncer-pd > 01/01/2015 > 30/11/2020 > 2015

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