Mitochondrial mutagenesis correlates with the local inflammatory environment in arthritis

Ann Rheum Dis. 2012 Apr;71(4):582-8. doi: 10.1136/annrheumdis-2011-200245. Epub 2011 Nov 25.


Background: To examine the association between mitochondrial mutagenesis and the proinflammatory microenvironment in patients with inflammatory arthritis.

Methods: Fifty patients with inflammatory arthritis underwent arthroscopy and synovial tissue biopsies, synovial fluid and clinical assessment were obtained. Fifteen patients pre/post-TNFi therapy were also recruited. Normal synovial biopsies were obtained from 10 subjects undergoing interventional arthroscopy. Macroscopic synovitis/vascularity was measured by visual analogue scale. Cell-specific markers CD3 (T cells) and CD68 (macrophages) were quantified by immunohistology. TNFα, IL-6, IFNγ and IL-1β were measured in synovial fluids by MSD multiplex assays. Synovial tissue mitochondrial mutagenesis was quantified using a mitochondrial random mutation capture assay (RMCA). The direct effect of TNFα on oxidative stress and mitochondrial function was assessed in primary cultures of rheumatoid arthritis synovial fibroblast cells (RASFCs). Mitochondrial mutagenesis, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and mitochondrial mass (MM) were quantified using the RMCA and specific cell fluorescent probes.

Results: A significant increase in mtDNA mutation frequency was demonstrated in inflamed synovial tissue compared with control (p<0.05), an effect that was independent of age. mtDNA mutations positively correlated with macroscopic synovitis (r=0.52, p<0.016), vascularity (r=0.54, p<0.01) and with synovial fluid cytokine levels of TNFα (r=0.74, p<0.024) and IFNγ (r=0.72, p<0.039). mtDNA mutation frequency post-TNFi therapy was significantly lower in patients with a DAS<3.2 (p<0.05) and associated with clinical and microscopic measures of disease (p<0.05). In vitro TNFα significantly induced mtDNA mutations, ROS, MM and MMP in RASFCs (all p<0.05).

Conclusion: High mitochondrial mutations are strongly associated with synovial inflammation showing a direct link between mitochondrial mutations and key proinflammatory pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antirheumatic Agents / pharmacology
  • Antirheumatic Agents / therapeutic use
  • Arthritis, Psoriatic / genetics
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / pathology
  • Arthroscopy
  • Biological Products / pharmacology
  • Biological Products / therapeutic use
  • Biopsy
  • Cells, Cultured
  • DNA, Mitochondrial / drug effects
  • DNA, Mitochondrial / genetics*
  • Female
  • Humans
  • Inflammation Mediators / metabolism
  • Male
  • Middle Aged
  • Mitochondria / drug effects
  • Mitochondria / physiology
  • Mutagenesis*
  • Mutation
  • Synovial Membrane / pathology
  • Synovitis / genetics
  • Synovitis / pathology
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / pharmacology


  • Antirheumatic Agents
  • Biological Products
  • DNA, Mitochondrial
  • Inflammation Mediators
  • Tumor Necrosis Factor-alpha