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
- Dylan G. Ryan
2025-11-20
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 Ala 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.