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PXD028460

PXD028460 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleGDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton
DescriptionCharcot-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 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. 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.
HostingRepositoryPRIDE
AnnounceDate2022-08-12
AnnouncementXMLSubmission_2022-08-12_00:24:27.127.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterDavid Gomez-Zepeda
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListmonohydroxylated residue; iodoacetamide derivatized residue
InstrumentSynapt MS
Dataset History
RevisionDatetimeStatusChangeLog Entry
02021-09-14 05:17:19ID requested
12022-08-12 00:24:27announced
Publication List
Wolf C, Pouya A, Bitar S, Pfeiffer A, Bueno D, Rojas-Charry L, Arndt S, Gomez-Zepeda D, Tenzer S, Bello FD, Vianello C, Ritz S, Schwirz J, Dobrindt K, Peitz M, Hanschmann EM, Mencke P, Boussaad I, Silies M, Br, ü, stle O, Giacomello M, Kr, ü, ger R, Methner A, GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton. Commun Biol, 5(1):541(2022) [pubmed]
Keyword List
submitter keyword: GDAP1, β-oxidation, LC-MS
Contact List
Stefan Tenzer
contact affiliationInstitute for Immunology, University Medical Center Mainz. Langenbeckstr. 1 55131 Mainz, Germany
contact emailtenzer@uni-mainz.de
lab head
David Gomez-Zepeda
contact affiliationUniversity Medical Center of the Johannes Gutenberg-University Mainz
contact emaildgomezze@uni-mainz.de
dataset submitter
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