# Mitochondrial dysfunction drives natural killer cell dysfunction in systemic lupus erythematosus

## TL;DR

This study finds that mitochondrial dysfunction in natural killer cells contributes to immune problems in systemic lupus erythematosus and suggests ways to restore function.

## Contribution

The study identifies mitochondrial dysfunction and impaired mitophagy as novel drivers of NK cell dysfunction in SLE.

## Key findings

- SLE NK cells accumulate enlarged and dysfunctional mitochondria with impaired lysosomal acidification.
- Transcriptional and proteomic analyses reveal downregulation of mitophagy-related genes and pathways.
- Urolithin A and hydroxychloroquine partially restore mitochondrial function and NK cell responses.

## Abstract

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.

This study links defective mitochondrial recycling to impaired natural killer cell function in SLE and identifies potential treatments to restore immune balance.