Identification and validation of PARK7 as a novel mitochondria-related signature associated with immune microenvironment in asthma

Background: Asthma is one of the most common respiratory diseases characterized by immune cell infiltration. However, the roles of mitochondria-related genes and their crosstalk with immune cell infiltration in asthma remain unclear. This study aimed to investigate the role and interaction of mitochondria-related genes and the immune cells in asthma through both bioinformatic analysis and experimental approaches.

Methods: The microarray data GSE76262 was obtained from NCBI GEO datasets, and differentially expressed genes (DEGs) were acquired by GEO2R. DAVID database was used for Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Mitochondrial genes were downloaded from Human MitoCarta3.0, and then Mitochondria-related DEGs (MitoDEGs) were obtained. STRING database was used to construct the Protein-Protein Interaction network, and then the hub genes were identified. The receiver operating characteristic curves were used to assess the diagnostic effects of hub genes in asthma patients. The infiltration of immune cells was analyzed by using the ImmuCellAI database. The expression of hub MitoDEGs was validated in an HDM-induced animal model. The compound-23 was utilized to investigate the function of PARK7 both in vivo and in vitro.

Results: Mitochondria were predicted to be involved in the pathology and physiology of asthma. The 47 MitoDEGs were identified, and three hub MitoDEGs (DNM1L, FIS1, and PARK7) were predicted to participate in asthma pathogenesis. Compared to DNM1L and FIS1, PARK7 had the most diagnostic effectiveness. The hub MitoDEGs were mainly positively associated with macrophages, monocytes, and CD8⁺T cells, while negatively associated with multiple CD4⁺T cells. Compared to the control group, the mRNA and protein expression levels of DNM1L, FIS1, and PARK7 were downregulated in the model group. Additionally, activating the function of PARK7 via compound-23 alleviated the mitochondrial damage, decreased the production of IL-25, IL-33, CCL17 and CCL20, subsequently improved the immune microenvironment and airway inflammation.

Conclusion: These results suggested that mitochondria-related genes were involved in the pathological processes of asthma, and verified the protective role of PARK7 in HDM-induced asthma models, which provided the potential insight into the clinical diagnosis and therapy of asthma.

Asthma; Diagnosis biomarkers; Immune cell infiltration; Mitochondria; PARK7.