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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.