Th141 - The Cellular Metabolism of SLE NK Cells Is Primarily Altered at the Level of Mitochondrial Homeostasis

Morgane Humbel – Immunology and allergy – Centre Hospitalier Universitaire Vaudois (CHUV) / Lausanne University Hospital; Camillo Ribi – Immunology and allergy – Centre Hospitalier Universitaire Vaudois (CHUV) / Lausanne University Hospital; Denis Comte – Immunology and allergy – Centre Hospitalier Universitaire Vaudois (CHUV) / Lausanne University Hospital

Abstract Text: Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease, in which the role of natural killer (NK) cells remains poorly understood. In patients with SLE, NK cells are decreased in number, exhibit reduced cytotoxicity and impaired cytokine production. Herein, we examined the metabolic alterations of human SLE NK cells, compared to healthy controls. Real-time metabolic assay showed that SLE NK cells mitochondrial respiration (OXPHOS) is significantly increased, while glycolysis is similar to healthy controls, suggesting alterations in mitochondrial homeostasis. Accordingly, we examined the mitochondrial fitness of SLE NK cells. We observed that mitochondrial mass is increased, while mitochondrial activity is decreased, suggesting an accumulation of dysfunctional mitochondria. Mitochondria of SLE NK cells displayed increased levels of superoxide, thereby predisposing them to mitochondrial damage, defective debris clearance, and apoptosis. There was no difference in mitochondrial DNA quantification between SLE NK cells and healthy controls, suggesting that mitochondria are increased in size but not in number. Transmission electron microscopy showed mitochondrial cristae disorganization in SLE NK cells. Quantitative proteomic analysis revealed that SLE NK cells express high levels of proteins associated with mitochondrial synthesis (TOM6) and OXPHOS (ATP synthase F(0), NADH deshydrogenase1 C1). In parallel, we observed a reduction in key proteins for mitochondrial clearance (such as E3 ubiquitin ligases: RNF181, MARCHF5), and lysosomal acidification (Proton-transporting V-Type ATPase). These results suggest an alteration in mitochondrial degradation (mitophagy) in SLE NK cells and suggest that impaired mitochondrial function and homeostasis represent a major feature of SLE pathogenesis.