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

Publikationstyp:
Zeitschriftenaufsatz
Metadaten:
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

Datenquelle: Crossref

Andere Metadatenquellen:
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

Datenquelle: 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

Datenquelle: 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

Datenquelle: OPENSCIENCE.UB

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