Figure 8.

Proposed effect of IFN/αRNP on neutrophil mitochondria. (left) MtDNA is normally found in complex with TFAM in the mitochondrial matrix of healthy neutrophils. In the steady state, mitochondria can undergo oxidative damage and/or depolarization (↓ΔΨ). While most cells remove damaged mitochondria through mitophagy, this process does not take place in neutrophils (1). Instead, healthy neutrophils extrude matrix components into the extracellular space (2). These include mtDNA–TFAM complexes devoid of Ox DNA. These complexes do not activate pDCs (3). MtDNA undergoing oxidation is removed through an alternative route. Thus, TFAM dissociates from it upon phosphorylation by the matrix-resident PKA (4). TFAM is then degraded and Ox mtDNA is sorted into vesicles directed to lysosomes (5). (right) In SLE, neutrophil activation with TLR7-agonist autoantibodies leads to decreased mitochondrial cAMP levels (6) and reduced matrix PKA activity. As a result, TFAM is not efficiently disassembled from Ox mtDNA. This leads to intramitochondrial retention and extrusion of Ox nucleoids. Extracellular Ox nucleoids activate pDCs in a TFAM/RAGE-dependent manner (7).