PXD057988

PXD057988 is an original dataset announced via ProteomeXchange.

Title	Inactivation of mitochondrial pyruvate dehydrogenase by singlet oxygen involves lipoic acid oxidation, side-chain modification and structural changes
Description	The multi-subunit pyruvate dehydrogenase complex (PDC) plays a crucial role in glucose oxidation as it determines whether pyruvate is used for mitochondrial oxidative phosphorylation, or is converted to lactate for aerobic glycolysis. PDC contains three lipoic acid groups, covalently attached at lysine residues to give lipoyllysine, which are responsible for acyl group transfer and critical to complex activity. We have recently reported that both free lipoic acid, and lipoyllysine in alpha-keto glutarate dehydrogenase, is highly susceptible to singlet oxygen (1O2)-induced oxidation. We therefore hypothesized that PDC activity and structure would be influenced by 1O2 (generated using Rose Bengal and light) via modification of the lipoyllysines and other residues. PDC activity was decreased by photooxidation, with this being dependent on light exposure, and the presence of O2, Rose Bengal, and D2O consistent with 1O2-mediated reactions. These changes were modulated by pre-illumination addition of free lipoic acid and lipoamide. Activity loss occurred concurrently with lipoyllysine and sidechain modification (determined by mass spectrometry) and protein aggregation (detected by SDS-PAGE). Peptide mass mapping provided evidence for modification at 43 residues (Met, Trp, His and Tyr; with modification extents of 20-50%) and all three lipoyllysine sites (6-20% modification). Structure modelling indicated the modifications occur across all 4 subunit types, and occur in functional domains or at multimer interfaces, consistent with damage at multiple sites contributing to the overall loss of activity. These data indicate that PDC activity and structure are highly susceptible to 1O2-induced damage with potential effects on cellular pathways of glucose metabolism.
HostingRepository	PRIDE
AnnounceDate	2025-05-28
AnnouncementXML	Submission_2025-05-28_12:32:14.923.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Per Hägglund
SpeciesList	scientific name: Sus scrofa domesticus (domestic pig); NCBI TaxID: 9825;
ModificationList	L-kynurenine; monohydroxylated residue; N6-lipoyl-L-lysine
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2024-11-18 06:55:12	ID requested
⏵ 1	2025-05-28 12:32:15	announced

10.1016/J.FREERADBIOMED.2025.04.011;

submitter keyword: photooxidation, lipoic acid,Pyruvate dehydrogenase, glucose metabolism

Per Hagglund and Michael Davies
contact affiliation	University of Copenhagen Faculty of Health and Medical Sciences Department of Biomedical Sciences Panum Institute Building 12.6 Blegdamsvej 3, 2200 Copenhagen N
contact email	hagglundperm@gmail.com
lab head
Per Hägglund
contact affiliation	University of Copenhagen
contact email	hagglundperm@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD057988
     1. Label: PRIDE project
     2. Name: Inactivation of mitochondrial pyruvate dehydrogenase by singlet oxygen involves lipoic acid oxidation, side-chain modification and structural changes