Mitochondrial transplantation ameliorates rheumatoid arthritis by targeting abnormal CGAS-STING1 signaling activation, autophagosome accumulation, and necroptosis

Mitochondrial damage in fibroblast-like synoviocytes (FLSs) is a key factor involved in the development and progression of rheumatoid arthritis (RA). In this study, we investigated the role of mitochondrial dysfunction of FLSs in the pathogenesis of RA. We induced inflammation by stimulating FLSs with TNF and IL17. Then, we transplanted fresh mitochondria into stimulated FLSs and evaluated the mitochondrial and lysosomal functions, macroautophagic/autophagic activity, and the STING1-associated cell death pathway. Next, we transplanted mitochondria or gold nanoparticle-conjugated mitochondria (GNP-Mito) into collagen-induced arthritis (CIA) mice and evaluated their therapeutic effects <i>in vivo</i>. Mitochondrial and lysosomal activities were decreased and autophagosomes accumulated in the stimulated FLSs. Furthermore, the STING1 signaling pathway and STING1-associated cell death were increased in the inflammatory condition. Mitochondrial transplantation into stimulated FLSs enhanced the mitochondrial and lysosomal activities and activated the autophagic activity, as demonstrated by decreased numbers of autophagosomes and increased numbers of autolysosomes. Mitochondrial transplantation decreased and increased the T_h17 and T_reg populations, respectively. Mitochondrial function and autophagic activity were enhanced by mitochondrial transplantation. Taken together, our results demonstrate that mitochondrial dysfunction in FLSs plays a pivotal role in the pathophysiology of RA and mitochondrial transplantation has therapeutic potential for RA development and progression.<b>Abbreviations</b>: ATP:adenosine triphosphate; CGAS: cyclic GMP-AMP synthase; CIA:collagen-induced arthritis; FLS: fibroblast-like synoviocytes; GNP:gold nanoparticle; ROS: reactive oxygen species; SQSTM1/p62:sequestosome 1; STING1: stimulator of interferon response cGAMPinteractor 1; MAP1LC3B/LC3B: microtubule associated protein 1 lightchain 3 beta.