Figure 2. Mitochondria in RA and SLE T cells.

RA T cells lose expression of MRE11, a nuclease functioning as a DNA repair molecule. Lack of mitochondrial MRE11A results in damage of mitochondrial DNA, increased susceptibility of mtDNA to oxidative damage and leakage of mtDNA into the cytoplasm. Cytoplasmic mtDNA is recognized as a danger associated molecular pattern (DAMP), initiates assembly of the inflammasome and activates caspase-1. As a result, T cells undergo pyroptotic cell death, release IL-1β and IL-18 and function as a nidus of tissue inflammation. In SLE T cells, mitochondrial biogenesis and fusion are enhanced while mitophagy is decreased. Thus, SLE T cells have high mitochondrial mass and elevated mitochondrial transmembrane potential [ΔΨm]. Inevitably, such T cells produce abundant ROS and exhaust cellular glutathione stores. The oxidative intracellular environment leads to cell death and drives mTORC1 activation. Downstream events of mTORC1 activation include recycling and lysosomal degradation of the T cell surface receptor/CD3ζ chain (TCRζ). Compensatory upregulation of the Fcε receptor type Iγ chain (FcεRIγ) and recruitment of tyrosine-protein kinase (Syk) enhance calcium fluxing, rendering these T cells hyper-reactive. MRE11, meiotic recombination 11; ROS, reactive oxygen species; GSH, glutathione; mTORC1, mammalian target of rapamycin complex 1.