PXD040504-1

PXD040504 is an original dataset announced via ProteomeXchange.

Title	NRF2 activation reprogrammes defects in oxidative metabolism to restore macrophage function in COPD
Description	Rationale: COPD (Chronic Obstructive Pulmonary Disease) is a disease characterized by persistent airway inflammation and disordered macrophage function. The extent to which alterations in macrophage bioenergetics contribute to impaired antioxidant responses and disease pathogenesis has yet to be fully delineated. Objectives: Through the study of COPD alveolar (AM) and peripheral monocyte-derived (MDM) macrophages, we sought to establish if intrinsic defects in core metabolic processes drive macrophage dysfunction and redox imbalance. Methods: AM and MDM from COPD and healthy donors underwent functional, metabolic and transcriptional profiling. Results: We observe that AM and MDM from COPD donors display a critical depletion in glycolytic and mitochondrial respiration derived energy reserves and an over reliance on glycolysis as a source for ATP, resulting in reduced energy status. Defects in oxidative metabolism extend to an impaired redox balance associated with defective expression of the NADPH generating enzyme, malic enzyme 1, a known target of the anti-oxidant transcription factor NRF2. Consequently, selective activation of NRF2 resets the COPD transcriptome, resulting in increased generation of TCA cycle intermediaries, improved energetic status, favorable redox balance and a recovery of macrophage function. Conclusion: In COPD an inherent loss of metabolic plasticity leads to metabolic exhaustion and reduced redox capacity which can be rescued by activation of the NRF2 pathway. Targeting these defects, via NRF2 augmentation, may therefore present an attractive therapeutic strategy for the treatment of the aberrant airway inflammation described in COPD.
HostingRepository	PRIDE
AnnounceDate	2024-10-07
AnnouncementXML	Submission_2024-10-07_11:14:42.967.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Andrew Howden
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2023-02-28 09:19:50	ID requested
⏵ 1	2024-10-07 11:14:43	announced
2	2024-10-22 05:44:33	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: metabolism, macrophage, malic enzyme 1.,Chronic obstructive pulmonary disease, nuclear factor erythroid 2–related factor 2 (NRF2)

Sarah R. Walmsley
contact affiliation	University of Edinburgh Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
contact email	sarah.walmsley@ed.ac.uk
lab head
Andrew Howden
contact affiliation	University of Dundee
contact email	a.howden@dundee.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD040504
     1. Label: PRIDE project
     2. Name: NRF2 activation reprogrammes defects in oxidative metabolism to restore macrophage function in COPD