2026/01/29 by Natalia Fluder, Morgane Humbel, Emeline Recazens +4 · 1 voice · 1 citation
Immunology and Microbiology · Medicine · #Autoimmune and Inflammatory Disorders Research #Autoimmunity #Autophagy in Disease and Therapy #Cytokine #Degranulation #Immune Cell Function and Interaction #Immune system #Inflammation #Innate immune system #Mitochondrion #Mitophagy #Natural killer cell
paper · pdf · doi:10.1172/jci.insight.195170
published in JCI Insight 11(5) (American Society for Clinical Investigation)
openalex publication_date 2026/01/29 · openalex created_date 2026/02/03 · openalex updated_date 2026/08/01
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation and widespread inflammation. NK cells display marked functional impairment in SLE, including defective cytotoxicity and cytokine production, but the underlying mechanisms remain poorly defined. Here, we show that mitochondrial dysfunction and impaired mitophagy are key contributors to NK cell abnormalities in SLE. Using complementary structural, metabolic, and proteomic analyses, we found that SLE NK cells accumulate enlarged and dysfunctional mitochondria, exhibit impaired lysosomal acidification, and release mitochondrial DNA into the cytosol - features consistent with defective mitochondrial quality control. Transcriptional and proteomic profiling revealed downregulation of key mitophagy-related genes and pathways. These abnormalities correlated with reduced NK cell degranulation and cytokine production. We then tested whether enhancing mitochondrial quality control could restore NK cell function. The mitophagy activator Urolithin A improved mitochondrial and lysosomal parameters and rescued NK cell effector responses in vitro. Hydroxychloroquine partially restored mitochondrial recycling and reduced cytosolic mtDNA. These findings suggest that defective mitophagy and mitochondrial dysfunction are major contributors to NK cell impairment in SLE and that targeting mitochondrial quality control may represent a promising strategy for restoring immune balance in this disease.