2. Academic Validation
  3. An inherited mitochondrial DNA mutation remodels inflammatory cytokine responses in macrophages and in vivo in mice

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

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.

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