Identification of key mitochondria-related genes and their relevance to the immune system linking Parkinson's disease and primary Sjögren's syndrome through integrated bioinformatics analyses

Yuan Zong; Yi Yang; Jiawen Zhao; Lei Li; Danyang Luo; Jiawei Hu; Yiming Gao; Xianfei Xie; Linhui Shen; Sheng Chen; Li Ning; Liting Jiang

doi:10.1016/j.compbiomed.2024.108511

Identification of key mitochondria-related genes and their relevance to the immune system linking Parkinson's disease and primary Sjögren's syndrome through integrated bioinformatics analyses

Comput Biol Med. 2024 Apr 23:175:108511. doi: 10.1016/j.compbiomed.2024.108511. Online ahead of print.

Authors

Yuan Zong¹, Yi Yang¹, Jiawen Zhao¹, Lei Li², Danyang Luo¹, Jiawei Hu¹, Yiming Gao¹, Xianfei Xie³, Linhui Shen⁴, Sheng Chen⁵, Li Ning⁶, Liting Jiang⁷

Affiliations

¹ Department of Stomatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China.
² Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Hainan Branch, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Qionghai, China; Department of Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Department of Geriatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ Department of Stomatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China. Electronic address: ln11448@rjh.com.cn.
⁷ Department of Stomatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China. Electronic address: jlt11392@rjh.com.cn.

PMID: 38677173
DOI: 10.1016/j.compbiomed.2024.108511

Abstract

Background: Mitochondria are the metabolic hubs of cells, regulating energy production and antigen presentation, which are essential for activation, proliferation, and function of immune cells. Recent evidence indicates that mitochondrial antigen presentation may have an impact on diseases such as Parkinson's disease (PD) and autoimmune diseases. However, there is limited knowledge about the mechanisms that regulate the presentation of mitochondrial antigens in these diseases.

Methods: In the current study, RNA sequencing was performed on labial minor salivary gland (LSG) from 25 patients with primary Sjögren's syndrome (pSS) and 14 non-pSS aged controls. Additionally, we obtained gene expression omnibus datasets associated with PD patients from NCBI Gene Expression Omnibus (GEO) databases. Single-sample Gene Set Enrichment Analysis (ssGSEA), ESTIMATE and Spearman correlations were conducted to explore the association between mitochondrial related genes and the immune system. Furthermore, we applied weighted Gene Co-expression Network Analysis (WGCNA) to identify hub mitochondria-related genes and investigate the correlated networks in both diseases. Single cell transcriptome analysis, immunohistochemical (IHC) staining and quantitative real-time PCR (qRT-PCR) were used to verify the activation of the hub mitochondria-related pathway. Pearson correlations and the CIBERSORT algorithms were employed to further reveal the correlation between hub mitochondria-related pathways and immune infiltration.

Results: The transcriptome analysis revealed the presence of overlapping mitochondria-related genes and mitochondrial DNA damage in patients with pSS and PD. Reactive oxygen species (ROS), the senescence marker p53, and the inflammatory markers CD45 and Bcl-2 were found to be regionally distributed in LSGs of pSS patients. WGCNA analysis identified the STING pathway as the central mitochondria-related pathway closely associated with the immune system. Single cell analysis, IHC staining, and qRT-PCR confirmed the activation of the STING pathway. Subsequent, bioinformatic analysis revealed the proportion of infiltrating immune cells in the STING-high and STING-low groups of pSS and PD. Furthermore, the study demonstrated the association of the STING pathway with innate and adaptive immune cells, as well as functional cells, in the immune microenvironment of PD and pSS.

Conclusion: Our study uncovered a central pathway that connects mitochondrial dysfunction and the immune microenvironment in PD and pSS, potentially offering valuable insights into therapeutic targets for these conditions.

Keywords: Mitochondria; Mitochondrial metabolism; Parkinson's disease; Primary Sjogren's syndrome (pSS); Transcriptome.