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GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton
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 u...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9166793/ https://www.ncbi.nlm.nih.gov/pubmed/35662277 http://dx.doi.org/10.1038/s42003-022-03487-6 |
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author | Wolf, Christina Pouya, Alireza Bitar, Sara Pfeiffer, Annika Bueno, Diones Rojas-Charry, Liliana Arndt, Sabine Gomez-Zepeda, David Tenzer, Stefan Bello, Federica Dal 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 |
author_facet | Wolf, Christina Pouya, Alireza Bitar, Sara Pfeiffer, Annika Bueno, Diones Rojas-Charry, Liliana Arndt, Sabine Gomez-Zepeda, David Tenzer, Stefan Bello, Federica Dal 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 |
author_sort | Wolf, Christina |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9166793 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-91667932022-06-05 GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton Wolf, Christina Pouya, Alireza Bitar, Sara Pfeiffer, Annika Bueno, Diones Rojas-Charry, Liliana Arndt, Sabine Gomez-Zepeda, David Tenzer, Stefan Bello, Federica Dal 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 Commun Biol Article 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. Nature Publishing Group UK 2022-06-03 /pmc/articles/PMC9166793/ /pubmed/35662277 http://dx.doi.org/10.1038/s42003-022-03487-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Wolf, Christina Pouya, Alireza Bitar, Sara Pfeiffer, Annika Bueno, Diones Rojas-Charry, Liliana Arndt, Sabine Gomez-Zepeda, David Tenzer, Stefan Bello, Federica Dal 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 GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton |
title | GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton |
title_full | GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton |
title_fullStr | GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton |
title_full_unstemmed | GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton |
title_short | GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton |
title_sort | gdap1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9166793/ https://www.ncbi.nlm.nih.gov/pubmed/35662277 http://dx.doi.org/10.1038/s42003-022-03487-6 |
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