PXD002991

PXD002991 is an original dataset announced via ProteomeXchange.

Title	Succination of Tubulin and VDAC2 in the Mouse Brainstem
Description	Elevated fumarate concentrations resulting from inhibition of the Krebs cycle lead to increases in protein succination, an irreversible post-translational modification that occurs when fumarate reacts with cysteine residues to generate S-(2-succino)cysteine (2SC). Metabolic events that reduce NADH reoxidation can block Krebs cycle activity, therefore we hypothesized that oxidative phosphorylation deficiencies such as those observed in mitochondrial diseases would also lead to increased protein succination. Using the Ndufs4 knockout (Ndufs4 KO) mouse, a model of Leigh syndrome, we demonstrate for the first time that protein succination is increased in the brainstem (BS), particularly the vestibular nucleus (VN). Notably, the brainstem is the most affected region exhibiting neurodegeneration and astrocyte and microglial proliferation, and these mice typically die of respiratory failure attributed to VN pathology. In contrast, no increases in protein succination were observed in the skeletal muscle, corresponding with the lack of muscle pathology observed in this model. 2D SDS-PAGE followed by immunoblotting for succinated proteins and MS/MS analysis of BS samples allowed us to identify the voltage-dependent anion channels (VDAC) 1 and 2 as specific targets of succination. Using targeted mass spectrometry, Cys77 was identified as a site of endogenous succination in VDAC2. Given the important role of VDAC isoforms in the exchange of ADP/ATP between the cytosol and the mitochondria, and the already decreased capacity for ATP synthesis in the Ndufs4 KO mice, we propose that the increased protein succination observed in the BS of these animals would further decrease the already compromised mitochondrial brain function. These data suggest that fumarate is a novel biochemical link that may contribute to the progression of the neuropathology in this mitochondrial disease model.
HostingRepository	PRIDE
AnnounceDate	2015-10-16
AnnouncementXML	Submission_2015-10-16_02:16:42.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD002991
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Allison Manuel
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2015-09-30 01:21:19	ID requested
⏵ 1	2015-10-16 02:16:43	announced

Piroli GG, Manuel AM, Clapper AC, Walla MD, Baatz JE, Palmiter RD, Quintana A, Frizzell N, Succination is Increased on Select Proteins in the Brainstem of the NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) Knockout Mouse, a Model of Leigh Syndrome. Mol Cell Proteomics, 15(2):445-61(2016) [pubmed]

curator keyword: Biomedical, Biological

submitter keyword: Succination Tubulin VDAC2

Norma Frizzell Catledge
contact affiliation	University of South Carolina School of Medicine
contact email	Norma.Frizzell@uscmed.sc.edu
lab head
Allison Manuel
contact affiliation	University of South Carolina School of Medicine
contact email	Allison.Manuel@uscmed.sc.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD002991
     1. Label: PRIDE project
     2. Name: Succination of Tubulin and VDAC2 in the Mouse Brainstem