Targeting the mitochondrial recycling dysfunction in systemic lupus erythematosus (SLE) patients NK cells with Hydroxychloroquine (HCQ)

ABSTRACT: Objectives: Natural Killer (NK) cell dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis, but its underlying mechanisms remain poorly understood. This study investigates immunometabolic alterations in NK cells from SLE patients and explores therapeutic strategies for their restoration. Methods: We characterized mitochondrial structure and function in NK cells from the peripheral blood of SLE patients and healthy controls using flow cytometry, electron microscopy, and proteomics. Key mitophagy-related gene expressions were quantified using qPCR. The therapeutic effects of hydroxychloroquine (HCQ) on mitochondrial recycling and NK cell function were assessed in vitro. Results: SLE NK cells were characterized by an accumulation of enlarged, hyperpolarized mitochondria with cristae disorganization, and reduced mitophagy. Impaired lysosomal acidification and mtDNA extrusion into the cytosol were also observed. Treatment with hydroxychloroquine restored lysosomal pH, mitochondrial recycling, and NK cell effector functions, including cytokine production and cytotoxicity. Conclusions: This study identifies mitochondrial recycling dysfunction as a driver of NK cell abnormalities in SLE and highlights the potential of HCQ to restore NK cell functionality. These findings provide new insights into the immunometabolic mechanisms underlying SLE and suggest avenues for targeted therapeutic interventions.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Natural Killer Cell

DISEASE(S): Systemic Lupus Erythematosus

SUBMITTER: Denis Comte  

LAB HEAD: Denis Comte

PROVIDER: PXD059825 | Pride | 2026-01-14

REPOSITORIES: Pride