TNF-α Induces Mitophagy in Rheumatoid Arthritis Synovial Fibroblasts, and Mitophagy Inhibition Alleviates Synovitis in Collagen Antibody-Induced Arthritis

Abstract

Mitophagy is a selective form of autophagy that removes damaged mitochondria. Increasing evidence indicates that dysregulated mitophagy is implicated in numerous autoimmune diseases, but the role of mitophagy in rheumatoid arthritis (RA) has not yet been reported. The aim of the present study was to determine the roles of mitophagy in patient-derived RA synovial fibroblasts (RASFs) and in the collagen antibody-induced arthritis mouse model. We measured the mitophagy marker PTEN-induced putative kinase 1 (PINK1) in RASFs treated with tumor necrosis factor-α (TNF-α) using Western blotting and immunofluorescence. Arthritis was induced in PINK1−/− mice by intraperitoneal injection of an anti-type II collagen antibody cocktail and lipopolysaccharide. RA severity was assessed by histopathology. PINK1 expression and damaged mitochondria increased in TNF-α treated RASFs via increased intracellular levels of reactive oxygen species. PINK1 knockdown RASFs decreased cellular migration and invasion functions. In addition, PINK1−/− mice with arthritis exhibited markedly reduced swelling and inflammation relative to wild-type mice with arthritis. Taken together, these findings suggest that regulation of PINK1 expression in RA could represent a potential therapeutic and diagnostic target for RA.

Ultrasound-Remote Selected Activation Mitophagy for Precise Treatment of Rheumatoid Arthritis by Two-Dimensional Piezoelectric Nanosheets

“…11,12 Therefore, inducing abnormal mitochondrial self-clearance, reducing the release of inflammatory factors, and limiting the inflammatory response are effective methods to break the vicious cycle and treat RA. 13 As a mitochondrial clearance mechanism, mitophagy plays a vital role in maintaining immune homeostasis and the pathogenesis of autoimmune diseases. 14−16 As a critical mode of mitophagy induction, the depolarized mitochondrial membrane potential (MMP) is formed by the proton pump on the mitochondrial respiratory chain that pumps H + from the mitochondrial matrix into the intermembrane space.…”

“…Among the many triggers of RA, oxidative stress mediated by excess reactive oxygen species (ROS) produced by abnormal mitochondria bears the brunt. , At the same time, the course of RA may be accompanied by excessive proliferation of synovial fibroblasts, leading to abnormal proliferation of synovial tissue, which again accumulates large amounts of abnormal mitochondria and produces large amounts of ROS and inflammatory factors, ultimately leading to a vicious cycle. , Therefore, inducing abnormal mitochondrial self-clearance, reducing the release of inflammatory factors, and limiting the inflammatory response are effective methods to break the vicious cycle and treat RA . As a mitochondrial clearance mechanism, mitophagy plays a vital role in maintaining immune homeostasis and the pathogenesis of autoimmune diseases. − As a critical mode of mitophagy induction, the depolarized mitochondrial membrane potential (MMP) is formed by the proton pump on the mitochondrial respiratory chain that pumps H + from the mitochondrial matrix into the intermembrane space.…”

Role of reactive oxygen species and mitochondrial damage in rheumatoid arthritis and targeted drugs

“…However, the effect of mitochondrial autophagy has two sides ( 120 , 121 ). On the one hand, promoting mitophagy can inhibit multiple pathological behaviors of FLSs and reduce the inflammatory response induced by mtDNA and ROS ( 122 – 124 ). On the other hand, mitochondrial autophagy, as a means for cells to deal with stress, may contribute to cell survival.…”

Redefining Autoimmune Disorders’ Pathoetiology: Implications for Mood and Psychotic Disorders’ Association with Neurodegenerative and Classical Autoimmune Disorders

“…Raised cerebrospinal fluid and plasma indicants of autophagy and mitophagy, including PINK1 and parkin, are evident in the active phase of relapse remitting multiple sclerosis, with autophagy inhibition enhancing myelination, highlighting that the enhancement, as well as the suppression, of mitophagy are aspects of 'autoimmune' disorders [53]. Dysregulated mitophagy is evident in many classical 'autoimmune' disorders, including rheumatoid arthritis [54], SLE [55], T1DM [56], myasthenia gravis [57] and autoimmune hepatitis [58], as well as in suspected 'autoimmune' conditions, such as endometriosis [59], and neurodegenerative conditions [60]. Notably, alterations in mitochondrial function and mitophagy are not always evident in cells classically associated with these conditions, but in cells relevant to wider intercellular interactions, including immune cell mitochondria, as evident in Treg in myasthenia gravis [57].…”