The DNA Repair Nuclease MRE11A Functions as a Mitochondrial Protector and Prevents T Cell Pyroptosis and Tissue Inflammation

Yinyin Li, Yi Shen, Ke Jin, Zhenke Wen, Wenqiang Cao, Bowen Wu, Ru Wen, Lu Tian, Gerald J. Berry, Jorg J. Goronzy, Cornelia M. Weyand

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

In the autoimmune disease rheumatoid arthritis (RA), CD4+ T cells promote pro-inflammatory effector functions by shunting glucose away from glycolysis and ATP production. Underlying mechanisms remain unknown, and here we implicate the DNA repair nuclease MRE11A in the cells’ bioenergetic failure. MRE11A deficiency in RA T cells disrupted mitochondrial oxygen consumption and suppressed ATP generation. Also, MRE11A loss of function caused leakage of mitochondrial DNA (mtDNA) into the cytosol, triggering inflammasome assembly, caspase-1 activation, and pyroptotic cell death. Caspase-1 activation was frequent in lymph-node-residing T cells in RA patients. In vivo, pharmacologic and genetic inhibition of MRE11A resulted in tissue deposition of mtDNA, caspase-1 proteolysis, and aggressive tissue inflammation. Conversely, MRE11A overexpression restored mitochondrial fitness and shielded tissue from inflammatory attack. Thus, the nuclease MRE11A regulates a mitochondrial protection program, and MRE11A deficiency leads to DNA repair defects, energy production, and failure and loss of tissue homeostasis. In rheumatoid arthritis, T cells are deficient in the DNA repair nuclease MRE11A and age prematurely. Li et al. show that MRE11A is necessary to sustain mitochondrial fitness and ATP production. T cells deficient in MRE11A leak mtDNA into the cytoplasm, triggering pyroptosis and driving tissue inflammation.

Original languageEnglish (US)
Pages (from-to)477-492.e6
JournalCell Metabolism
Volume30
Issue number3
DOIs
StatePublished - Sep 3 2019

Keywords

  • ATP
  • caspase-1
  • DNA damage repair
  • inflammasome
  • mitochondrial DNA
  • MRE11A
  • pyroptosis
  • rheumatoid arthritis
  • T cell aging
  • tissue inflammation

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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