PXD066893

PXD066893 is an original dataset announced via ProteomeXchange.

Title	Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology
Description	Neurodegenerative disorders alter mitochondrial functions, including the production of reactive oxygen species (ROS). Mitochondrial complex III (CIII) generates ROS implicated in redox signaling, but its triggers, temporal dynamics, targets, and disease relevance are not clear. Using site-selective suppressors and genetic manipulations together with live mitochondrial ROS imaging and multiomic profiling, we found that CIII is a dominant source of ROS production in astrocytes exposed to neuropathology-related stimuli. Astrocytic CIII-ROS production was dependent on nuclear factor-κB (NF-κB) and the mitochondrial sodium-calcium exchanger (NCLX) and caused oxidation of select cysteines within immune- and metabolism-associated proteins linked to neurological disease. CIII-ROS amplified metabolomic and pathology-associated transcriptional changes in astrocytes, with STAT3 activity as a major mediator, and facilitated neuronal toxicity. Therapeutic suppression of CIII-ROS in mice decreased dementia-linked tauopathy and neuroimmune cascades and extended lifespan. Our findings establish CIII-ROS as an important immunometabolic signal transducer and tractable therapeutic target in neurodegenerative disease.
HostingRepository	PRIDE
AnnounceDate	2025-09-05
AnnouncementXML	Submission_2025-09-05_06:50:11.279.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Daniel Barnett
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-08-03 12:47:15	ID requested
⏵ 1	2025-09-05 06:50:12	announced

10.1101/2024.08.19.608708;

Barnett D, Zimmer TS, Booraem C, Palaguachi F, Meadows SM, Xiao H, Chouchani ET, Orr AG, Orr AL, Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology. bioRxiv, ():(2024) [pubmed]

submitter keyword: Cysteine proteomics,Mouse, Astrocyte, LC-MS/MS

Adam Orr
contact affiliation	Appel Alzheimer's Disease Research Institute Feil Family Brain and Mind Research Institute Weill Cornell Medicine New York, NY 10021
contact email	alo2012@med.cornell.edu
lab head
Daniel Barnett
contact affiliation	Weill Cornell Medicine
contact email	dmb4001@med.cornell.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/09/PXD066893

PRIDE project URI

• PRIDE
  1. PXD066893
     1. Label: PRIDE project
     2. Name: Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology