Nat Commun. 2025 Nov 20. 16(1): 10222
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.
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.