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

  • Nat Commun. 2025 Nov 20;16(1):10222. doi: 10.1038/s41467-025-65023-4.
Eloïse Marques  1 ,  Stephen P Burr  1 ,  Alva M Casey  1 ,  Richard J Stopforth  2  3 ,  Chak Shun Yu  1 ,  Keira Turner  1 ,  Dane M Wolf  1 ,  Marisa Dilucca  4 ,  Vincent Paupe  1 ,  Suvagata Roy Chowdhury  1 ,  Victoria J Tyrrell  5 ,  Robbin Kramer  1 ,  Yamini M Kanse  1 ,  Chinmayi Pednekar  6 ,  Chris A Powell  1 ,  James B Stewart  7 ,  Julien Prudent  1 ,  Michael P Murphy  1 ,  Michal Minczuk  1  8 ,  Valerie B O'Donnell  5 ,  Clare E Bryant  4 ,  Patrick F Chinnery  1  8 ,  Arthur Kaser  2  3 ,  Alexander von Kriegsheim  6 ,  Dylan G Ryan  9  10
Affiliations
  • 1. MRC Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • 2. Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK.
  • 3. Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
  • 4. Department of Medicine, Addenbrooke's hospital, Cambridge Biomedical Campus, Cambridge, UK.
  • 5. Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
  • 6. Cancer Research UK Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  • 7. Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
  • 8. Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • 9. MRC Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK. [email protected].
  • 10. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland. [email protected].
PMID: 41266309 DOI: 10.1038/s41467-025-65023-4
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.

Products