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

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

doi:10.1016/j.cmet.2019.06.016

Cited by 112 publications

(104 citation statements)

References 49 publications

(60 reference statements)

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“…MRE11A loss of function results in a metabolic phenotype, with marked reduction of mitochondrial oxygen consumption and ATP generation (Figure ). How can the double‐strand break repair nuclease interfere with metabolic competence of T cells?…”

Section: Ra T Cells Lose the Mitochondrial Protector Mre11amentioning

confidence: 99%

“…Cytoplasmic MRE11A has been implicated in DNA sensing . Mitochondrial MRE11A binds to mitochondrial DNA (mtDNA), and genetic or pharmacologic inhibition of MRE11A causes leakage of mtDNA into the cytoplasm . Leaked mtDNA is then recognized by the NLRP3 and the AIM2 inflammasome to trigger procaspase‐1 cleavage.…”

Section: Ra T Cells Lose the Mitochondrial Protector Mre11amentioning

confidence: 99%

Section: Ra T Cells Misplace Amp‐activated Protein Kinase (Ampk) To Nmentioning

confidence: 99%

“…51 Mitochondrial MRE11A binds to mitochondrial DNA (mtDNA), and genetic or pharmacologic inhibition of MRE11A causes leakage of mtDNA into the cytoplasm. 49 Leaked mtDNA is then recognized by the NLRP3 and the AIM2 inflammasome to trigger procaspase-1 cleavage. MRE11A-dependent inflammasome assembly and caspase-1 activation lead to IL-1β release, but more importantly, give rise to pyroptotic T-cell death.…”

Section: R a T Cell S Los E The Mitochondrial Protec Tor Mre11 Amentioning

confidence: 99%

“…While mitochondrial oxygen consumption is markedly repressed in RA T cells, mitochondrial mass is maintained and is indistinguishable from that in healthy T cells. However, stability and containment of mtDNA is compromised in the patient-derived T cells 49. Despite the low ATP generation and the high AMP:ATP ratio in RA T cells, AMPK is not activated, crippling a fundamental pathway to secure energy homeostasis.…”

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confidence: 99%

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Immunometabolism in the development of rheumatoid arthritis

Weyand

Goronzy

2020

Immunological Reviews

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100

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In rheumatoid arthritis (RA), breakdown of self‐tolerance and onset of clinical disease are separated in time and space, supporting a multi‐hit model in which emergence of autoreactive T cells is a pinnacle pathogenic event. Determining factors in T cell differentiation and survival include antigen recognition, but also the metabolic machinery that provides energy and biosynthetic molecules for cell building. Studies in patients with RA have yielded a disease‐specific metabolic signature, which enables naive CD4 T cells to differentiate into pro‐inflammatory helper T cells that are prone to invade into tissue and elicit inflammation through immunogenic cell death. A typifying property of RA CD4 T cells is the shunting of glucose away from glycolytic breakdown and mitochondrial processing toward the pentose phosphate pathway, favoring anabolic over catabolic reactions. Key defects have been localized to the mitochondria and the lysosome; including instability of mitochondrial DNA due to the lack of the DNA repair nuclease MRE11A and inefficient lysosomal tethering of AMPK due to deficiency of N‐myristoyltransferase 1 (NMT1). The molecular taxonomy of the metabolically reprogrammed RA T cells includes glycolytic enzymes (glucose‐6‐phosphate dehydrogenase, phosphofructokinase), DNA repair molecules (MRE11A, ATM), regulators of protein trafficking (NMT1), and the membrane adapter protein TSK5. As the mechanisms determining abnormal T cell behavior in RA are unraveled, opportunities will emerge to interject autoimmune T cells by targeting their metabolic checkpoints.

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Section: Ra T Cells Lose the Mitochondrial Protector Mre11amentioning

confidence: 99%

Section: Ra T Cells Lose the Mitochondrial Protector Mre11amentioning

confidence: 99%

Section: Ra T Cells Misplace Amp‐activated Protein Kinase (Ampk) To Nmentioning

confidence: 99%

Section: R a T Cell S Los E The Mitochondrial Protec Tor Mre11 Amentioning

confidence: 99%

mentioning

confidence: 99%

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Immunometabolism in the development of rheumatoid arthritis

Weyand

Goronzy

2020

Immunological Reviews

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100

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Redox Pathogenesis in Rheumatic Diseases

Laniak,

Winans,

Patel

et al. 2024

ACR Open Rheumatology

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Despite being some of the most anecdotally well‐known roads to pathogenesis, the mechanisms governing autoimmune rheumatic diseases are not yet fully understood. The overactivation of the cellular immune system and the characteristic development of autoantibodies have been linked to oxidative stress. Typical clinical manifestations, such as joint swelling and deformities and inflammation of the skin and internal organs, have also been connected directly or indirectly to redox mechanisms. The differences in generation and restraint of oxidative stress provide compelling evidence for the broad variety in pathology among rheumatic diseases and explain some of the common triggers and discordant manifestations in these diseases. Growing evidence of redox mechanisms in pathogenesis has provided a broad array of new potential therapeutic targets. Here, we explore the mechanisms by which oxidative stress is generated, explore its roles in autoimmunity and end‐organ damage, and discuss how individual rheumatic diseases exhibit unique features that offer targets for therapeutic interventions.

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Obeticholic Acid Inhibit Mitochondria Dysfunction Via Regulating ERK1/2‐DRP Pathway to Exert Protective Effect on Lipopolysaccharide‐Induced Myocardial Injury

Miao,

Tang,

Cui

et al. 2024

Advanced Biology

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Farnesoid X receptor (FXR) plays critical regulatory roles in cardiovascular physiology/pathology. However, the role of FXR agonist obeticholic acid (OCA) in sepsis‐associated myocardial injury and underlying mechanisms remain unclear. C57BL/6J mice are treated with OCA before lipopolysaccharide (LPS) administration. The histopathology of the heart and assessment of FXR expression and mitochondria function are performed. To explore the underlying mechanisms, H9c2 cells, and primary cardiomyocytes are pre‐treated with OCA before LPS treatment, and extracellular signal‐regulated protein kinase (ERK) inhibitor PD98059 is used. LPS‐induced myocardial injury in mice is significantly improved by OCA pretreatment. Mechanistically, OCA pretreatment decreased reactive oxygen species (ROS) levels and blocked the loss of mitochondrial membrane potential (ΔΨm) in cardiomyocytes. The expression of glutathione peroxidase 1 (GPX1), superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2), and nuclear factor erythroid 2‐related factor 2 (NRF‐2) increased in the case of OCA pretreatment. In addition, OCA improved mitochondria respiratory chain with increasing Complex I expression and decreasing cytochrome C (Cyt‐C) diffusion. Moreover, OCA pretreatment inhibited LPS‐induced mitochondria dysfunction via suppressing ERK1/2‐DRP signaling pathway. FXR agonist OCA inhibits LPS‐induced mitochondria dysfunction via suppressing ERK1/2‐DRP signaling pathway to protect mice against LPS‐induced myocardial injury.

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

Abstract: Highlights d The DNA repair nuclease MRE11A is located in mitochondria d Mitochondrial MRE11A protects mtDNA from oxidation and cytoplasmic leakage d MRE11A low T cells fail to produce ATP and undergo caspase-1-dependent pyroptosis d MRE11A loss of function results in tissue inflammation

Cited by 112 publications

References 49 publications

Immunometabolism in the development of rheumatoid arthritis

Immunometabolism in the development of rheumatoid arthritis

Redox Pathogenesis in Rheumatic Diseases

Obeticholic Acid Inhibit Mitochondria Dysfunction Via Regulating ERK1/2‐DRP Pathway to Exert Protective Effect on Lipopolysaccharide‐Induced Myocardial Injury

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