Multiple mitochondrial dysfunctions, such as increased mitochondrial reactive oxygen species (mROS), depolarized membrane potential, altered morphology, and changes in energy production, were observed in patients with systemic lupus erythematosus (SLE), suggesting that mitochondrial function plays a role in lupus pathogenesis. Calcium is an essential regulator of mitochondrial functions, and when macrophages become polarized, their metabolism is reprogrammed based on their phenotypes. The connection between mitochondrial calcium mobilization and lupus remains unclear. In this study, we explored the expression and function of the mitochondrial calcium uniporter (MCU) in monocytes/macrophages in lupus pathogenesis. We examined the ex vivo gene expression profiles of human renal biopsies with nephropathies, SLE whole blood, peripheral blood mononuclear cells (PBMCs), and mouse renal macrophages, identifying a decrease in MCU- related genes in Lupus nephritis and other inflammatory nephropathies. We also found that the expression of MCU-related genes significantly decreased in monocytes and macrophages stimulated with LPS and also upon M1/2 polarization, both from healthy controls and patients with SLE. Lastly, we generated hematopoietic and endothelial cell specific MCU knockout mice and used a pristane-induced lupus model to test in vivo the role of MCU in lupus development. Interestingly, there was no significant difference in disease severity between MCU knockout mice and wild-type mice, indicating that the absence of MCU did not improve nor worsen lupus pathology in mice. Since the LPS-induced down-regulation of MCU-related genes, found in human cells, was not consistently reproducible in murine macrophages, these results suggest a species-specific regulation of MCU-related genes in innate immunity.

In conclusion, this study provides valuable insights on the reduction of mitochondrial function during monocytes/macrophages activation and in lupus nephritis. Although a causal link between MCU and lupus remains unclear, these results support further research to fully understand the complex relationship between mitochondrial function, calcium mobilization, and lupus pathogenesis.