PXD028460
PXD028460 is an original dataset announced via ProteomeXchange.
Dataset Summary
Title | GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton |
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 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. |
HostingRepository | PRIDE |
AnnounceDate | 2022-08-12 |
AnnouncementXML | Submission_2022-08-12_00:24:27.127.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | David Gomez-Zepeda |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | monohydroxylated residue; iodoacetamide derivatized residue |
Instrument | Synapt MS |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
---|---|---|---|
0 | 2021-09-14 05:17:19 | ID requested | |
⏵ 1 | 2022-08-12 00:24:27 | announced |
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 affiliation | Institute for Immunology, University Medical Center Mainz. Langenbeckstr. 1 55131 Mainz, Germany |
contact email | tenzer@uni-mainz.de |
lab head | |
David Gomez-Zepeda | |
contact affiliation | University Medical Center of the Johannes Gutenberg-University Mainz |
contact email | dgomezze@uni-mainz.de |
dataset submitter |
Full Dataset Link List
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PRIDE project URI |
Repository Record List
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