Figure 4.

Connection between oxidized mtDNA and Lupus. Stimulation of IFN-treated neutrophils or neutrophils from lupus patients with anti-RNP immune complexes can lead to release of oxidized (ox) mtDNA by multiple mechanisms: 1) Stimulation of NETosis, with extrusion of DNA containing oxidized mtDNA. 2) Increased mitochondrial ROS leads to membrane translocation and extrusion of oxidized mtDNA into the extracellular milieu. 3) Anti-RNP and type I IFN decrease the levels of cyclic AMP (cAMP), a second messenger required for activation of protein kinase A (PKA), which normally phosphorylates TFAM, enabling its release from mtDNA. When TFAM is released, the mtDNA can then go to the lysosome for degradation. If PKA is inhibited, TFAM remains associated with mtDNA in nucleoids that accumulate in mitochondria and then are released from the neutrophils through unclear mechanisms. Extracellular oxidized mtDNA is sensed by monocytes in a STING-dependent manner and internalized by pDC via RAGE receptors. Downstream of RAGE, the IFN-generating sensor in pDC is unclear, although both oxidized and non-oxidized mtDNA stimulation of pDC is TLR9-dependent (139). The abundance of anti-mtDNA antibodies in lupus and correlation with disease support the critical involvement of these mechanisms in disease pathogenesis (137, 139, and 140).