Identification of Mitofusin 1 and Complement Component 1q Subcomponent Binding Protein as Mitochondrial Targets in Systemic Lupus Erythematosus

Abstract

Objective Mitochondria are organelles that exhibit several bacterial features, such as a double‐stranded genome with hypomethylated CpG islands, formylated proteins, and cardiolipin‐containing membranes. In systemic lupus erythematosus (SLE), mitochondria and their inner components are released into the extracellular space, potentially eliciting a proinflammatory response from the immune system. While cardiolipin and mitochondrial DNA and RNA are confirmed targets of autoantibodies, other antigenic mitochondrial proteins in SLE remain to be identified. The present study was undertaken to characterize the protein repertoire recognized by antimitochondrial antibodies (AMAs) in patients with SLE. Methods Using shotgun proteomic profiling, we identified 1,345 proteins, 431 of which were associated with the mitochondrial proteome. Immunoreactivities to several of these candidate proteins were assessed in serum samples from a local cohort (n = 30 healthy donors and 87 patients with SLE) using enzyme‐linked immunosorbent assay, and further analyzed for associations with demographic and disease characteristics. Results We determined that IgG antibodies to the complement component C1q binding protein were significantly elevated in the patients with SLE (P = 0.049) and were also associated with lupus anticoagulant positivity (P = 0.049). Elevated levels of IgG antibodies against mitochondrial protein mitofusin 1 (MFN‐1) were promising predictors of SLE diagnosis in our cohort (adjusted odds ratio 2.99 [95% confidence interval 1.39–6.43], P = 0.0044). Moreover, increased levels of anti–MFN‐1 were associated with the presence of antiphospholipids (P = 0.011) and anti–double‐stranded DNA (P = 0.0005). Conclusion In this study, we characterized the mitochondrial repertoire targeted by AMAs in the setting of SLE. Our results indicate that autoantibodies can recognize secreted and/or surface proteins of mitochondrial origin. Profiling of the AMA repertoire in large prospective cohorts may improve our knowledge of mitochondrial biomarkers and their usefulness for patient stratification.

An update on autoantibodies in systemic lupus erythematosus

“…Among MOM proteins, Mitofusin-1 (MFN-1) was confirmed as a target of AMA in SLE. Interestingly, both anti-C1qBP and anti-MFN-1 antibodies were associated with anti-cardiolipin antibodies, and anti-MFN-1 was associated with anti-B2GPI and anti-dsDNA antibodies [47 ▪▪ ]. It is worth to note that the association of antibodies to C1qBP and MFN-1 with antibodies to cardiolipin (an antigen also found in mitochondria) is intriguing and may suggest that these antibodies are markers of pathogenic pathways involving mitochondrial damage in patients with SLE.…”

“…Anti-mitochondrial antibodies (AMAs) have been described in SLE, including antibodies to the mitochondrial outer membrane (MOM), mitochondrial DNA (mtDNA), mitochondrial RNA (mtRNA) and heat shock protein 60 (Hsp60), among others [45,46]. In a recent article, Becker et al explored the spectrum of proteins targeted by AMA in SLE by using mass spectrometry analysis of mitochondrial proteins immunoprecipitated by SLE serum [47 ▪▪ ]. Two complementary sources of mitochondrial antigens were applied to this approach.…”

Metabolic alterations of the immune system in the pathogenesis of autoimmune diseases

“…Additionally, enhanced mitochondrial activity and autoantibody production by long-lived memory B cells in SLE may be facilitated by deficient peroxiredoxin 6 (PRDX6) antioxidant activity [ 40 ] and by an intact mitochondrial cardiolipin remodeling enzyme activity provided by tafazzin [ 41 ]. In SLE, mitochondrial dysfunction might also promote the formation and externalization of mitochondria-derived autoantigens recognized by B cells, including mitofusin 1 and complement component 1q subcomponent-binding proteins [ 42 ]. Dysfunctional mitochondria that acquire somatic mDNA mutations via cumulative mROS damage may promote subsequent generation of modified self-peptides, breaching tolerance [ 43 ].…”

Platelet extracellular vesicles and the secretory interactome join forces in health and disease

“…These antibodies, such as antimitochondrial DNA, anti-mitochondrial RNA, anti-cardiolipin, and proteins from the mitochondrial outer membrane (mitofusin-1), are reported in systemic lupus erythematosus and anti-phospholipid syndrome. [144][145][146][147][148][149] Antibodies against mitochondria are also well described in primary biliary cirrhosis. 150 In sum, extracellular mitochondria produced by activated platelets can be immunogenic and may provide an important source of circulating autoantigens critical in disease development.…”

“…Intriguingly, autoreactive B‐cells produce antibodies that target diverse components of the mitochondria. These antibodies, such as anti‐mitochondrial DNA, anti‐mitochondrial RNA, anti‐cardiolipin, and proteins from the mitochondrial outer membrane (mitofusin‐1), are reported in systemic lupus erythematosus and anti‐phospholipid syndrome 144–149 . Antibodies against mitochondria are also well described in primary biliary cirrhosis 150 .…”