GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton
- Publication type:
- Journal article
- Metadata:
-
- Abstract
- <jats:title>Abstract</jats:title><jats:p>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<jats:sup>2+</jats:sup> homeostasis. Here, we identify the underlying mechanism. We found that patient-derived motoneurons and <jats:italic>GDAP1</jats:italic> 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<jats:sup>2+</jats:sup> 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.</jats:p>
- Autoren
- Christina Wolf
- Alireza Pouya
- Sara Bitar
- Annika Pfeiffer
- Diones Bueno
- Liliana Rojas-Charry
- Sabine Arndt
- David Gomez-Zepeda
- Stefan Tenzer
- Federica Dal Bello
- Caterina Vianello
- Sandra Ritz
- Jonas Schwirz
- Kristina Dobrindt
- Michael Peitz
- Eva-Maria Hanschmann
- Pauline Mencke
- Ibrahim Boussaad
- Marion Silies
- Oliver Brüstle
- Marta Giacomello
- Rejko Krüger
- Axel Methner
- DOI
- 10.1038/s42003-022-03487-6
- eISSN
- 2399-3642
- Ausgabe der Veröffentlichung
- 1
- Zeitschrift
- Communications Biology
- Sprache
- en
- Artikelnummer
- 541
- Online publication date
- 2022
- Status
- Published online
- Herausgeber
- Springer Science and Business Media LLC
- Herausgeber URL
- http://dx.doi.org/10.1038/s42003-022-03487-6
- Datum der Datenerfassung
- 2022
- Titel
- GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton
- Ausgabe der Zeitschrift
- 5
Data source: Crossref
- Other metadata sources:
-
- 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 Ca<sup>2+</sup> 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<sup>2+</sup> 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.
- Addresses
- Institute of Molecular Medicine, University Medical Center Mainz, Mainz, Germany.
- Autoren
- Christina Wolf
- Alireza Pouya
- Sara Bitar
- Annika Pfeiffer
- Diones Bueno
- Liliana Rojas-Charry
- Sabine Arndt
- David Gomez-Zepeda
- Stefan Tenzer
- Federica Dal Bello
- Caterina Vianello
- Sandra Ritz
- Jonas Schwirz
- Kristina Dobrindt
- Michael Peitz
- Eva-Maria Hanschmann
- Pauline Mencke
- Ibrahim Boussaad
- Marion Silies
- Oliver Brüstle
- Marta Giacomello
- Rejko Krüger
- Axel Methner
- DOI
- 10.1038/s42003-022-03487-6
- eISSN
- 2399-3642
- Externe Identifier
- PubMed Identifier: 35662277
- PubMed Central ID: PMC9166793
- Funding acknowledgements
- Deutsche Forschungsgemeinschaft: ME1922 16-1
- Open access
- true
- ISSN
- 2399-3642
- Ausgabe der Veröffentlichung
- 1
- Zeitschrift
- Communications biology
- Schlüsselwörter
- Mitochondria
- Humans
- Neuroblastoma
- Pyruvate Dehydrogenase Complex
- Actins
- Nerve Tissue Proteins
- Actin Cytoskeleton
- Sprache
- eng
- Medium
- Electronic
- Online publication date
- 2022
- Open access status
- Open Access
- Paginierung
- 541
- Datum der Veröffentlichung
- 2022
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2022
- Titel
- GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton.
- Sub types
- Research Support, Non-U.S. Gov't
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 5
Files
https://www.nature.com/articles/s42003-022-03487-6.pdf https://europepmc.org/articles/PMC9166793?pdf=render
Data source: Europe PubMed Central
- 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.
- Date of acceptance
- 2022
- Autoren
- Christina Wolf
- Alireza Pouya
- Sara Bitar
- Annika Pfeiffer
- Diones Bueno
- Liliana Rojas-Charry
- Sabine Arndt
- David Gomez-Zepeda
- Stefan Tenzer
- Federica Dal Bello
- Caterina Vianello
- Sandra Ritz
- Jonas Schwirz
- Kristina Dobrindt
- Michael Peitz
- Eva-Maria Hanschmann
- Pauline Mencke
- Ibrahim Boussaad
- Marion Silies
- Oliver Brüstle
- Marta Giacomello
- Rejko Krüger
- Axel Methner
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/35662277
- DOI
- 10.1038/s42003-022-03487-6
- eISSN
- 2399-3642
- Externe Identifier
- PubMed Central ID: PMC9166793
- Ausgabe der Veröffentlichung
- 1
- Zeitschrift
- Commun Biol
- Schlüsselwörter
- Actin Cytoskeleton
- Actins
- Humans
- Mitochondria
- Nerve Tissue Proteins
- Neuroblastoma
- Pyruvate Dehydrogenase Complex
- Sprache
- eng
- Country
- England
- Paginierung
- 541
- PII
- 10.1038/s42003-022-03487-6
- Datum der Veröffentlichung
- 2022
- Status
- Published online
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2022
- Titel
- GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton.
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 5
Data source: PubMed
- Author's licence
- CC-BY
- Autoren
- Christina Wolf
- Alireza Pouya
- Sara Bitar
- Annika Pfeiffer
- Diones Bueno
- Liliana Rojas-Charry
- Sabine Arndt
- David Gomez-Zepeda
- Stefan Tenzer
- Federica Dal Bello
- Caterina Vianello
- Sandra Ritz
- Jonas Schwirz
- Kristina Dobrindt
- Michael Peitz
- Eva-Maria Hanschmann
- Pauline Mencke
- Ibrahim Boussaad
- Marion Silies
- Oliver Brüstle
- Marta Giacomello
- Rejko Krüger
- Axel Methner
- Hosting institution
- Universitätsbibliothek Mainz
- Sammlungen
- DFG-491381577-G
- Resource version
- Published version
- DOI
- 10.1038/s42003-022-03487-6
- Funding acknowledgements
- Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 491381577
- File(s) embargoed
- false
- Open access
- true
- ISSN
- 2399-3642
- Zeitschrift
- Communications biology
- Schlüsselwörter
- 610 Medizin
- 610 Medical sciences
- Sprache
- eng
- Open access status
- Open Access
- Paginierung
- 541
- Datum der Veröffentlichung
- 2022
- Public URL
- https://openscience.ub.uni-mainz.de/handle/20.500.12030/8811
- Herausgeber
- BioMed Central
- Datum der Datenerfassung
- 2023
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2023
- Zugang
- Public
- Titel
- GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton
- Ausgabe der Zeitschrift
- 5
Files
gdap1_loss_of_function_inhibi-20230210101611363.pdf
Data source: OPENSCIENCE.UB
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