An inherited mitochondrial DNA mutation remodels inflammatory cytokine responses in macrophages and in vivo in mice

Eloïse Marques, Stephen P. Burr, Alva M. Casey, Richard J. Stopforth, Chak Shun Yu, Keira Turner, Dane M. Wolf, Marisa Dilucca, Vincent Paupe, Suvagata Roy Chowdhury, Victoria J. Tyrrell, Robbin Kramer, Yamini M. Kanse, Chinmayi Pednekar, Chris A. Powell, James B. Stewart, Julien Prudent, Michael P. Murphy, Michal Minczuk, Valerie B. O’Donnell, Clare E. Bryant, Patrick F. Chinnery, Arthur Kaser, Alexander von Kriegsheim and Dylan G. Ryan ()
Additional contact information
Eloïse Marques: Cambridge Biomedical Campus, MRC Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge
Stephen P. Burr: Cambridge Biomedical Campus, MRC Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge
Alva M. Casey: Cambridge Biomedical Campus, MRC Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge
Richard J. Stopforth: University of Cambridge, Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre
Chak Shun Yu: Cambridge Biomedical Campus, MRC Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge
Keira Turner: Cambridge Biomedical Campus, MRC Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge
Dane M. Wolf: Cambridge Biomedical Campus, MRC Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge
Marisa Dilucca: Cambridge Biomedical Campus, Department of Medicine, Addenbrooke’s hospital
Vincent Paupe: Cambridge Biomedical Campus, MRC Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge
Suvagata Roy Chowdhury: Cambridge Biomedical Campus, MRC Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge
Victoria J. Tyrrell: Cardiff University, Division of Infection and Immunity, School of Medicine
Robbin Kramer: Cambridge Biomedical Campus, MRC Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge
Yamini M. Kanse: Cambridge Biomedical Campus, MRC Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge
Chinmayi Pednekar: University of Edinburgh, Cancer Research UK Centre, Institute of Genetics and Cancer
Chris A. Powell: Cambridge Biomedical Campus, MRC Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge
James B. Stewart: Newcastle University, Biosciences Institute, Faculty of Medical Sciences
Julien Prudent: Cambridge Biomedical Campus, MRC Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge
Michael P. Murphy: Cambridge Biomedical Campus, MRC Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge
Michal Minczuk: Cambridge Biomedical Campus, MRC Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge
Valerie B. O’Donnell: Cardiff University, Division of Infection and Immunity, School of Medicine
Clare E. Bryant: Cambridge Biomedical Campus, Department of Medicine, Addenbrooke’s hospital
Patrick F. Chinnery: Cambridge Biomedical Campus, MRC Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge
Arthur Kaser: University of Cambridge, Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre
Alexander von Kriegsheim: University of Edinburgh, Cancer Research UK Centre, Institute of Genetics and Cancer
Dylan G. Ryan: Cambridge Biomedical Campus, MRC Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge

Nature Communications, 2025, vol. 16, issue 1, 1-24

Abstract: Abstract 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.

Date: 2025
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-65023-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65023-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-65023-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().