We recently described a fundamental role for mitochondrial-mediated inflammation in systemic lupus erythematosus. Briefly, mitochondrial ROS promoted release of mitochondria and oxidized mitochondrial DNA inducing prominent IFN-beta production through the cGAS-STING pathway propagating disease in lupus-prone mice. However, although known to promote inflammation, mechanisms contributing to mitochondrial clearance have not been investigated. The overall aims of the present study are to investigate molecular events participating in the clearance of mitochondria in lupus pathogenesis as well as identifying mitochondrial biomarkers associated with disease activity and severity. In the first aim we will investigate if lupus patients have increased levels of cell-free mitochondria and their relation to inflammatory markers, as well as disease activity and severity. In the second aim we will assess mitochondrial clearance, in particular phagocytosis and cytokine induction, by myeloid cells. As complement components are known to regulate uptake and inflammatory properties of apoptotic cells and immune complexes, we will determine the role of complement in mitochondrial clearance and inflammatory potential. Finally, we will characterize anti-mitochondrial antibodies in SLE patients, including their inflammatory potential and capacity to stratify patients based on disease phenotype. In summary, the current research will provide novel, much needed, insight into mitochondrial-mediated inflammation and autoimmunity in lupus patients.