New insights from Mendelian randomization and mediation analysis: causal relationships between mitochondrial DNA copy number and telomere length in pulmonary fibrosis

BACKGROUND: Variations in mitochondrial DNA (mtDNA) copy number can lead to mitochondrial dysfunction, subsequently accelerating cellular senescence, a process implicated in the pathogenesis of multiple respiratory diseases. However, the causal relationship between mitochondrial DNA copy number and respiratory diseases, as well as the potential mediating factors involved, remains to be fully elucidated. OBJECTIVE: This study aimed to establish the causal link between mtDNA copy number and pulmonary diseases and to explore the potential mediating role of telomere length in this association. METHODS: Univariate Mendelian randomization (UVMR) analyses were conducted to assess the relationships among mitochondrial DNA copy number, respiratory diseases, and telomere length in immune cells. To refine the causal inference, multivariable Mendelian randomization (MVMR) was employed. The mediating effect of telomere length on the causal pathway between mitochondrial DNA copy number and pulmonary diseases was specifically investigated. RESULTS: UVMR analysis revealed a significant causal association between mitochondrial DNA copy number (n = 395 718) and pulmonary fibrosis (n = 469 126). In the MVMR model, the genetic associations among mitochondrial DNA copy number, Naïve T-cell telomere length, and pulmonary fibrosis remained robust. Importantly, Naïve T-cell telomere length was identified as a critical mediator in the causal pathway linking mtDNA copy number to pulmonary fibrosis. CONCLUSIONS: This study provides genetic evidence supporting a causal relationship between reduced mitochondrial DNA copy number and increased risk of pulmonary fibrosis. It also highlights Naïve T-cell telomere length as a key intermediary factor in this process. Nonetheless, further in vivo and in vitro investigations are needed to validate these findings and to elucidate the underlying molecular mechanisms.