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

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 tRNA<sup>Ala</sup> 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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Publication Details

Journal
Nature Communications
Published
2025-11-20
DOI
https://doi.org/10.1038/s41467-025-65023-4
Citations
2
Primary Topic
interferon and immune responses
Type
article
Field-Weighted Citation Impact
1.59

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article

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

Keira Turner, Patrick Francis Chinnery, James B. Stewart, Victoria J. Tyrrell et al.
2 citations
Nature Communications
interferon and immune responses
1.59
article

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

Keira Turner, Patrick Francis Chinnery, James B. Stewart, Victoria J. Tyrrell, Alva M. Casey, Christopher A. Powell, Michal A. Minczuk, Eloïse Marques, Dane M. Wolf, Richard J Stopforth, Stephen P. Burr, Alex von Kriegsheim, Arthur Kaser, Clare Elizabeth Bryant, Chak Shun Yu, Valerie B. O’Donnell, Julien Prudent, Chinmayi Pednekar, Michael P. Murphy, Marisa Dilucca, Dylan G. Ryan, Robbin Kramer, Vincent Paupe, Suvagata Roy Chowdhury, Yamini M Kanse
article en
2 citations

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 tRNA<sup>Ala</sup> 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.

Nature CommunicationsVol. 16(1)
Trinity College (CA), Trinity College Dublin (IE), University of Cambridge (GB), Edinburgh Cancer Research (GB), Addenbrooke's Hospital (GB), MRC Epidemiology Unit (GB), MRC Mitochondrial Biology Unit (GB), Cardiff University (GB), Newcastle University (GB)
Leona M. and Harry B. Helmsley Charitable Trust, Wellcome Trust, UK Research and Innovation, Medical Research Council, Cambridge Institute for Medical Research, University of Cambridge
Openalex Percentile: Top 14%
interferon and immune responses
1.59
DOIOpen Access PDFOpenAlex
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