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, Christopher A. Powell, James B. Stewart, Julien Prudent, Michael P. Murphy, Michal Minczuk, Valerie B. O’Donnell, Clare Bryant, Patrick F. Chinnery, Arthur Kaser, Alex von Kriegsheim, Dylan G. Ryan
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 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.