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<p>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 (<i>m.5019A</i>&gt;<i>G</i>) 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, <i>m.5019A</i>&gt;<i>G</i> 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 <i>m.5019A</i>&gt;<i>G</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月20日

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  • 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

摘要

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.