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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Impaired mitochondrial bioenergetics in macrophages promotes hyperinflammatory cytokine responses, but whether inherited mtDNA mutations drive similar phenotypes is unknown. Here, we profiled macrophages harbouring a heteroplasmic mitochondrial tRNAAla mutation (m.5019A>G) to address this question. These macrophages exhibit combined respiratory chain defects, reduced oxidative phosphorylation, disrupted cristae architecture, and compensatory metabolic adaptations in central carbon metabolism. Upon inflammatory activation, m.5019A>G macrophages produce elevated type I interferon (IFN), while exhibiting reduced pro-inflammatory cytokines and oxylipins. Mechanistically, suppression of pro-IL-1β and COX2 requires autocrine IFN-β signalling. IFN-β induction is biphasic: an early TLR4-IRF3 driven phase, and a later response involving mitochondrial nucleic acids and the cGAS-STING pathway. In vivo, lipopolysaccharide (LPS) challenge of m.5019A>G mice results in elevated type I IFN signalling and exacerbated sickness behaviour. These findings reveal that a pathogenic mtDNA mutation promotes an imbalanced innate immune response, which has potential implications for the progression of pathology in mtDNA disease patients.
Author(s): Marques E, Burr SP, Casey AM, Stopforth RJ, Yu CS, Turner K, Wolf DM, Dilucca M, Paup V, Choudhury SR, Tyrrell VJ, Kramer R, Kanse YM, Pednekar C, Powell CA, Stewart JB, Prudent J, Murphy MP, Minczuk M, O'Donnell V, Bryant CE, Chinnery PF, Kaser A, von Kriegsheim A, Ryan DG
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2025
Volume: 16
Issue: 4
Online publication date: 20/11/2025
Acceptance date: 06/10/2025
Date deposited: 21/11/2025
ISSN (electronic): 2041-1723
Publisher: Nature Publishing Group
URL: https://doi.org/10.1038/s41467-025-65023-4
DOI: 10.1038/s41467-025-65023-4
Data Access Statement: The RNA-sequencing datasets generated in this study have been deposited in Dryad under accession https://doi.org/10.5061/dryad.ksn02v7fn and in ArrayExpress under accession code E-MTAB-15591 (https://www.ebi.ac.uk/biostudies/arrayexpress/studies?query=E-MTAB-15591). The proteomics datasets have been deposited in PRIDE under accession code PXD060284 (https://www.ebi.ac.uk/pride/archive/projects/PXD060284). The raw lipidomics dataset has been deposited in the Cardiff University Research Data Repository (https://doi.org/10.17035/cardiff.30074749), together with the Oxylipin scheduled multiple reaction monitoring (sMRM) method report (https://doi.org/10.5281/zenodo.17078883). The raw metabolomics datasets have been deposited in MassIVE under accession code MSV000099126 (https://doi.org/10.25345/C58C9RH3G). All other data are available in the article and its Supplementary files or from the corresponding author upon request. Source data are provided in this paper.
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