Evidence of biological aging through mitochondrial DNA damage and dysregulation of mitophagy-related genes in veterans with delayed sulfur mustard toxicity.

Abstract

Sulfur mustard (SM) is a potent alkylating agent known to cause long-term health effects, including accelerated aging. This study investigated mitochondrial dysfunction as a key mechanism underlying biological aging in 142 SM-exposed veterans (25 years post-exposure) and 54 matched controls. The SM-exposed veterans were stratified into subgroups (asymptom, mild, and severe) based on clinical criteria and lung function tests. Using buffy coat-derived leukocytes, we assessed mitochondrial DNA (mtDNA) copy number and damage frequency of long/short mtDNA fragments, and mitophagy-related gene expression (PINK1, PRKN, DRP1, FIS1). Demographic variables (age, marital status, income, smoking status, education) did not differ significantly between SM-exposed and control groups, ensuring comparability. Results showed no significant differences in mtDNA copy number between groups; however, mtDNA damage frequency was significantly elevated in the severe exposure subgroup. Gene expression analysis revealed significantly increased mRNA levels of PINK1, PRKN, DRP1, and FIS1 in SM-exposed veterans compared to controls, with the highest expression observed in the severe and mild subgroups, while PINK1 expression showed no significant subgroup differences. These findings demonstrate that SM exposure induces persistent mitochondrial dysfunction through cumulative mtDNA damage, dysregulated mitophagy signaling, and aberrant fission activation. While preserved mtDNA copy numbers suggest adaptive biogenesis, the severity-dependent patterns in fission genes and mtDNA lesions establish mitochondrial impairment as a central pathway in SM-related aging.