Tributyl phosphate induces liver aging via fumarate-mediated mitochondrial DNA escape triggered FPR2 activation

Liver aging-induced failure and dysfunction in other organs constitute a critical aging phenotype that is distinct from chronological aging. Unlike intrinsic aging, hepatic senescence is predominantly driven by environmental factors. Tributyl phosphate (TBP) was identified as a potential key environmental trigger of liver aging; however, the underlying mechanisms remain largely elusive.

Rats and BRL-3A cells were treated with TBP. Serum metabolomics, liver proteomics, hepatocyte ultrastructure, β-galactosidase (β-GAL) activity, cell cycle progression, ROS and senescence-associated secretory phenotype (SASP) levels, as well as protein related to chromatin remodeling and DNA damage were used to evaluate liver aging. WRW4, ethidium bromide (EB), Lv-FH and monomethyl fumarate were utilized respectively to establish models of FPR2 inhibition, cytoplasmic mitochondrial DNA (mtDNA) depletion. fumarate clearance and supplied supplementation.

TBP induced cell cycle arrest, increased β-GAL activity, and elevated ROS and MMP-1 levels while upregulating p53, lys9, and γ-H2A.X protein expression. Additionally, TBP inhibited HP1 protein expression in rat livers and cells(P < 0.05). Significant changes in metabolites and proteins following TBP exposure were enriched in aging-related pathways. After treating with, WRW4, EB, Lv/sh-FH and monomethyl fumarate respectively, these changes were all reversed in BRL-3A cells (P < 0.05).

This study elucidat the effect of fumarate-mediated mtDNA escape in liver aging induced by TBP. We found that exposure to TBP induces the levels of fumarate, which directly drives mtDNA escape and activates the FPR2, finally triggers liver aging of rats.