Identification of Mitofusin 1 and Complement Component 1q Subcomponent Binding Protein as Mitochondrial Targets in
Yann L C Becker1, Jean-Philippe Gagné2, Anne-Sophie Julien3
1Centre de Recherche ARThrite, Axe Maladies infectieuses et immunitaires, Université Laval, Quebec City, Quebec, Canada.
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.
Insights
Researchers identified novel mitochondrial protein targets of autoantibodies in systemic lupus erythematosus (SLE). Elevated antibodies against mitofusin 1 (MFN-1) show promise as biomarkers for SLE diagnosis and disease activity.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Mitochondria possess bacterial features and are implicated in systemic lupus erythematosus (SLE) pathogenesis.
- Extracellular release of mitochondrial components in SLE can trigger immune responses.
- While cardiolipin, mitochondrial DNA, and RNA are known autoantibody targets, other antigenic mitochondrial proteins in SLE require identification.
Purpose of the Study:
- To characterize the protein repertoire recognized by antimitochondrial antibodies (AMAs) in patients with SLE.
- To identify novel mitochondrial autoantigens in SLE.
Main Methods:
- Shotgun proteomic profiling to identify mitochondrial proteins.
- Enzyme-linked immunosorbent assay (ELISA) to assess immunoreactivity to candidate proteins in patient serum.
- Analysis of associations between autoantibody levels and demographic/disease characteristics.
Main Results:
- Identified 1,345 proteins, with 431 linked to the mitochondrial proteome.
- Significantly elevated IgG antibodies to complement component C1q binding protein in SLE patients, associated with lupus anticoagulant positivity.
- Elevated anti-mitofusin 1 (MFN-1) IgG antibodies were significant predictors of SLE diagnosis (aOR 2.99) and associated with antiphospholipid and anti-dsDNA antibodies.
Conclusions:
- Autoantibodies in SLE can target secreted and/or surface mitochondrial proteins.
- Anti-MFN-1 antibodies may serve as potential biomarkers for SLE.
- Further profiling of AMA repertoires in large cohorts could enhance understanding of mitochondrial biomarkers for patient stratification.
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