Hydroxychloroquine corrects mitochondrial recycling dysfunction in natural killer cells from patients with systemic lupus erythematosus
Authors: Fluder Natalia , Humbel Morgane , Recazens Emeline , Jourdain Alexis A. , Ribi Camillo , Tsokos George C. , Comte Denis 
Published: January 2025

ABSTRACTObjectivesNatural Killer (NK) cell dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis, but the underlying mechanisms remain poorly understood. This study investigates immunometabolic alterations in NK cells from SLE patients and explores therapeutic strategies for their restoration.MethodsWe 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 ability of hydroxychloroquine (HCQ) to restore mitochondrial recycling and NK cell function were assessedin vitro.ResultsSLE NK cells displayed accumulated enlarged, hyperpolarized mitochondria with cristae disorganization, and reduced mitophagy. Impaired lysosomal acidification and mtDNA extrusion into the cytosol were also observed. Treatment with HCQ restored mitochondrial recycling, and NK cell effector functions, including cytokine production and cytotoxicity by acidifying lysosomes.ConclusionsThis study identifies mitochondrial recycling dysfunction as a driver of NK cell abnormalities in SLE patients. HCQ can correct these abnormalities by acidifying the lysosomes 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.WHAT IS KNOWN ON THE TOPIC➢ SLE is a complex inflammatory disease characterized by the development of autoreactive cells and a breakdown of self-tolerance (1, 2).➢ Natural Killer (NK) cells, pivotal players in the innate immune system, exhibit reduced numbers, diminished cytotoxicity, and impaired cytokine production in SLE patients (3-5).➢ Peripheral CD56dimCD57+NK cells from SLE patients exhibit increased endogenous apoptosis and higher levels of mitochondrial (mt)ROS, contributing to their altered function (6).WHAT THE STUDY ADDS➢ This study reveals a full spectrum of immunometabolic alterations in Natural Killer (NK) cells from SLE patients, including hyperpolarized mitochondria accumulation, cristae disorganization and impaired mitophagy. These results identify mitochondrial recycling dysfunction as a central factor in NK cell abnormalities in SLE.➢ It demonstrates for the first time that hydroxychloroquine (HCQ), a standard treatment for SLE, effectively restores mitochondrial recycling in NK cells by modulating lysosomal acidification, reducing cytosolic leakage of mtDNA and enhancing the expression of mitophagy-related genes.➢ These results highlight a new mechanism by which HCQ attenuates immune dysregulation, making it a potential targeted approach for treating the specific dysfunction of NK cells in SLE.HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY➢ Understanding how mitochondrial recycling dysfunction impacts SLE pathogenesis can pave the way for the development of targeted therapies and improved disease management for SLE patients.