Mitochondrial Dysfunction in Systemic Sclerosis

Objectives Systemic sclerosis (SSc) is a chronic inflammatory and fibrotic disease with the involvement of skin at its onset. Although numerous pathogenic processes contribute to SSc, its root cause remains poorly understood. We hypothesize that valuable insights into SSc pathogenesis can be gained by characterizing interactions between functional niches within the skin from SSc patients using spatial transcriptomics. We aimed to: 1. To identify and map functional zones in SSc skin based on their cellular composition and patterns of mRNA expression. 2. To objectively designate dominant molecular signatures and pathways to those discrete dermal zones using bioinformatic tools. Methods Skin biopsies from 11 patients with limited and diffuse cutaneous SSc were analyzed using spatial transcriptomic sequencing. Single-cell RNA sequencing (scRNA-seq)[1] were used to deconvolve dermal cell types. Sequencing reads were processed using Space Ranger and Cell Ranger pipelines. Clustering spatial and single-cell data was performed with Seurat. Identified clusters were annotated by differentially expressed genes, with functional enrichment analysis conducted using GO and KEGG pipelines via ClusterProfiler. Results Spatial transcriptomic analysis identified 6 distinct transcriptomic clusters spanning the dermis in an interwoven pattern not aligned with the histological layers of the skin. We focused on 3 major dermal clusters (designated as clusters 0, 1, and 4) comprising >90% of the dermal area. Cluster 0 was heterogeneous with respect to cell types, included inflammatory signature, and was functionally dominated by mitochondrial metabolic pathways. Cluster 1 contained mostly fibroblasts exhibiting fibrotic pathways with minimal inflammation. Cluster 4 represented perivascular areas with prominent smooth muscle cells and myofibroblast signatures. The mitochondrial gene dysregulation in cluster 0 showed downregulation of nuclear DNA-encoded mitochondrial genes and upregulation of mitochondrial DNA-encoded genes, indicating stress-adaptation mechanisms in this functional zone. In contrast, Cluster 1 exhibited downregulation of both nuclear and mitochondrial genes - suggesting complete collapse of mitochondrial function (Figure). Conclusion For the first time, we revealed discrete zones in SSc skin characterized by inflammation accompanied by mitochondrial stress, separated from the areas of fibrosis where the mitochondrial function was disintegrated. Our study supports previous research indicating that dysregulated mitochondria are central, if not fundamental, to the pathogenesis of SSc. [1.] Tabib T. Nat Commun 2021;12:4384.

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