Mitochondrial Bioenergetic Failure in SLE Immunocytes: Targeting Fitness for Therapy

Abstract

BackgroundSystemic Lupus Erythematosus (SLE) is characterized by dysregulated immune responses linked to immunometabolic perturbations. While mitochondrial dysfunction has been implicated in SLE, its cell-type-specific impact on immune subsets remains underexplored. MethodsWe repurposed existing RNA-seq data from SLE patient peripheral blood mononuclear cells, with a focus on nuclear-encoded mitochondrial (NEmt) genes, as well as mitochondrial genes themselves, to identify differentially expressed genes compared to healthy controls. Mitochondrial stress tests were performed on freshly isolated CD4+ T cells, CD8+ T cells, B cells, and monocytes from SLE patients and healthy donors to assess bioenergetic function. ResultsRNA-seq revealed that both NEmt genes and mitochondrial genes were downregulated in the PBMC population of SLE patients. In situ mitochondrial stress tests revealed significant reductions in oxygen consumption rate (OCR), indicating impaired oxidative phosphorylation (OXPHOS) across all immune subsets, while extracellular acidification rate (ECAR), a marker of glycolysis, remained unchanged. These findings highlight immune-cell-specific mitochondrial bioenergetic failure in SLE, without compensatory glycolytic adaptation. ConclusionOur results position mitochondrial fitness as a novel therapeutic target in SLE. We propose leveraging high-throughput screening of mitochondria-targeted compounds, including FDA-approved agents, to enhance OXPHOS, regulate mitophagy, or mitigate oxidative stress. This precision-based approach offers a paradigm shift from conventional immunosuppression to metabolic recalibration, with the potential to restore immune homeostasis in SLE. Key messagesO_LIWhat is already known on this topic: Mitochondrial dysfunction and metabolic reprogramming have been linked to SLE pathogenesis, but the cell-type-specific extent of mitochondrial impairment and its therapeutic potential remained unclear. C_LIO_LIWhat this study adds: We demonstrate reduced OXPHOS in CD4+ T cells, CD8+ T cells, B cells, and monocytes from SLE patients for the first time, highlighting cell-type-specific mitochondrial dysfunction as a possible driver of immune dysregulation and target for therapy. C_LIO_LIHow this study might affect research, practice, or policy: This study advocates for drug repurposing to restore mitochondrial fitness, offering a novel therapeutic strategy to complement existing SLE treatments and improve patient outcomes. C_LI