PXD024555-1

PXD024555 is an original dataset announced via ProteomeXchange.

Title	1GDAP1 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 GDAP1knockdown SH-SY5Y cells display two phenotypes: more tubular mitochondria and a metabolismcharacterized by glutamine dependence and fewer cytosoliclipid 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_02:57:24.090.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Malte Sielaff
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	iodoacetamide derivatized residue
Instrument	Synapt MS

Revision	Datetime	Status	ChangeLog Entry
0	2021-03-05 08:52:42	ID requested
⏵ 1	2022-08-12 02:57:25	announced

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]

submitter keyword: Mouse, Primary cortical neurons, GDAP1, Pulldown, SP3, LC-UDMSE

Stefan Tenzer
contact affiliation	University Medical Center Mainz, Germany, Institute for Immunology
contact email	tenzer@uni-mainz.de
lab head
Malte Sielaff
contact affiliation	University Medical Center Mainz
contact email	malte.sielaff@uni-mainz.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024555
     1. Label: PRIDE project
     2. Name: 1GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton