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

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          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 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.

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          Author and article information

          Journal
          Cell Metabolism
          Cell Metabolism
          Elsevier BV
          15504131
          July 2019
          July 2019
          Article
          10.1016/j.cmet.2019.06.016
          7093039
          31327667
          27977833-adb9-42cd-8c9f-7f87a8b15e12
          © 2019

          https://www.elsevier.com/tdm/userlicense/1.0/

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