GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton.

Autor: Wolf C; Institute of Molecular Medicine, University Medical Center Mainz, Mainz, Germany., Pouya A; Institute of Molecular Medicine, University Medical Center Mainz, Mainz, Germany., Bitar S; Institute of Molecular Medicine, University Medical Center Mainz, Mainz, Germany., Pfeiffer A; Institute of Molecular Medicine, University Medical Center Mainz, Mainz, Germany., Bueno D; Institute of Molecular Medicine, University Medical Center Mainz, Mainz, Germany., Rojas-Charry L; Institute of Molecular Medicine, University Medical Center Mainz, Mainz, Germany., Arndt S; Institute for Immunology, University Medical Center Mainz, Mainz, Germany., Gomez-Zepeda D; Institute for Immunology, University Medical Center Mainz, Mainz, Germany., Tenzer S; Institute for Immunology, University Medical Center Mainz, Mainz, Germany., Bello FD; Institute of Molecular Medicine, University Medical Center Mainz, Mainz, Germany.; Department of Biology, University of Padova, Padova, Italy.; Department of Biomedical Sciences, University of Padova, Padova, Italy., Vianello C; Institute of Molecular Medicine, University Medical Center Mainz, Mainz, Germany.; Department of Biology, University of Padova, Padova, Italy.; Department of Biomedical Sciences, University of Padova, Padova, Italy., Ritz S; Institute of Molecular Biology (IMB) gGmbH, Mainz, Germany., Schwirz J; Institute of Molecular Biology (IMB) gGmbH, Mainz, Germany., Dobrindt K; Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty and University Hospital Bonn, Bonn, Germany., Peitz M; Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty and University Hospital Bonn, Bonn, Germany.; Cell Programming Core Facility, University of Bonn School of Medicine, Bonn, Germany., Hanschmann EM; Department of Neurology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany., Mencke P; Translational Neuroscience, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg., Boussaad I; Translational Neuroscience, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg.; Disease Modeling and Screening Platform (DMSP), Luxembourg Centre of Systems Biomedicine (Biomedicine), University of Luxembourg and Luxembourg Institute of Health (LIH), Belvaux, Luxembourg., Silies M; Institute of Development Biology and Neurobiology, Johannes Gutenberg-University Mainz, Mainz, Germany., Brüstle O; Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty and University Hospital Bonn, Bonn, Germany., Giacomello M; Department of Biology, University of Padova, Padova, Italy.; Department of Biomedical Sciences, University of Padova, Padova, Italy., Krüger R; Translational Neuroscience, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg.; Transversal Translational Medicine, Luxembourg Institute of Health (LIH), Strassen, Luxembourg., Methner A; Institute of Molecular Medicine, University Medical Center Mainz, Mainz, Germany. axel.methner@gmail.com.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2022 Jun 03; Vol. 5 (1), pp. 541. Date of Electronic Publication: 2022 Jun 03.
DOI: 10.1038/s42003-022-03487-6
Abstrakt: 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 Ca 2+ 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 Ca 2+ 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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