美国斯坦福大学医学院Cornelia M. Weyand研究组发现DNA修复核酸酶MRE11A可参与保护线粒体并防止T细胞焦亡与组织炎症。这一研究成果发表在2019年9月3日出版的国际学术期刊《细胞—代谢》上。

据研究人员介绍，在自身免疫性疾病类风湿性关节炎（RA）中，CD4 阳性T细胞通过将葡萄糖分流远离糖酵解和ATP产生来促进促炎效应子功能。

这其中潜在的机制仍然未知，研究人员发现DNA修复核酸酶MRE11A在细胞的生物能量衰竭中有作用。RA T细胞中的MRE11A缺乏破坏了线粒体氧消耗并抑制了ATP的产生。此外，MRE11A功能丧失导致线粒体DNA（mtDNA）泄漏到胞质中，从而引发炎性小体组装、caspase-1活化和细胞焦亡。RA患者的淋巴结驻留T细胞中caspase-1活化频繁。在体内，MRE11A的药理和遗传抑制导致mtDNA的组织沉积、caspase-1蛋白水解和侵袭性组织炎症。相反，MRE11A过表达可恢复线粒体适应性并使得组织免受炎症发作。因此，核酸酶MRE11A调节线粒体保护程序，并且MRE11A缺乏导致DNA修复缺陷、能量产生以及组织稳态丧失。

附：英文原文

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

Author: Jorg J. Goronzy, Cornelia M. Weyand, et al

Issue&Volume: Volume 30 Issue 3

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.

DOI: https://doi.org/10.1016/j.cmet.2019.06.016

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30319-5