PXD060284-1

PXD060284 is an original dataset announced via ProteomeXchange.

Title	An inherited mtDNA mutation remodels inflammatory cytokine responses in macrophages and in vivo
Description	Impaired mitochondrial bioenergetics in macrophages can drive hyperinflammatory cytokine responses1–6, but whether this may also be caused by inherited mtDNA mutations is unknown. Here, we address this question using a multi-omic approach that integrates super-resolution imaging and metabolic analyses to profile macrophages from a mouse model of mitochondrial disease arising from a heteroplasmic mutation (m.5019A>G) in the mitochondrial tRNA for alanine7. These m.5019A>G macrophages exhibit defects in respiratory chain complexes and oxidative phosphorylation (OxPhos) due to decreased intra-mitochondrial translation. To adapt to this metabolic stress, mitochondrial fusion, reductive glutamine metabolism, and aerobic glycolysis are all increased. Upon inflammatory activation, type I interferon (IFN-I) release is enhanced, while the production of pro-inflammatory cytokines and oxylipins are restrained in m.5019A>G macrophages. Finally, an in vivo endotoxemia model using m.5019A>G mice reveal elevated IFN-I levels and sickness behaviour. In conclusion, our study identifies an unexpected imbalance in innate immune signalling in response to a pathogenic mtDNA mutation, with important implications for the progression of pathology in patients with mtDNA diseases
HostingRepository	PRIDE
AnnounceDate	2025-09-17
AnnouncementXML	Submission_2025-09-17_15:12:03.104.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alex von Kriegsheim
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-01-28 07:46:58	ID requested
⏵ 1	2025-09-17 15:12:03	announced

Dataset with its publication pending

submitter keyword: cytokine, metabolims,Macrophage

Dylan Ryan
contact affiliation	U o Cambridge
contact email	dr523@cam.ac.uk
lab head
Alex von Kriegsheim
contact affiliation	University of Edinburgh
contact email	alex.vonkriegsheim@ed.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD060284
     1. Label: PRIDE project
     2. Name: An inherited mtDNA mutation remodels inflammatory cytokine responses in macrophages and in vivo