Multi-Omics Analysis Links Mitochondrial-Related Genes to Idiopathic Pulmonary Fibrosis and In Vivo Transcriptome Validation

Abstract

Mitochondrial dysfunction is closely associated with idiopathic pulmonary fibrosis (IPF). However, the causal association between mitochondria-related genes and IPF remains to be determined. We obtained gene expression, protein abundance, and methylation quantitative trait locus data for mitochondria-related genes from previous studies. Genome-wide association study data for patients with IPF were obtained from the FinnGen study. A two-sample Mendelian randomisation analysis was conducted to assess the association between mitochondria-related genes and IPF. Furthermore, we conducted validation of expression differences utilizing transcriptome data derived from the BLM-induced pulmonary fibrosis mouse model (n=15). Concurrently, multiphoton imaging was utilized to quantify collagen contents and structural assessment. The direction of causality was verified using the Steiger test, and colocalisation analysis was used to better validate causality. Single-cell data were used to explore the localisation and expression of positive genes across different cell types. The study identified significant associations between mitochondria-related genes and IPF, with POLG and NDUFB10 classified as Grade 1; LYRM4, NBR1, and ACSF3 as Grade 2; MCL1, GFER, MFN2, IVD, and SLC25A35 as Grade 3; and METAP1D and MTX1 as Grade 4. Single-cell analysis showed elevated expression of NBR1, MCL1, and MTX1 in pulmonary myofibroblasts of IPF. This study elucidated the causal effects of mitochondria-related genes on IPF, underscoring their significance in pathogenesis. These findings contribute to an improved understanding of the mechanisms underlying IPF, offering new potential therapeutic targets for interventions.