ADSC-Exosomes Preserve Mitochondrial Function and Ameliorate Uranyl Acetate-Induced Nephrotoxicity Through Inhibition of ATF4 and Activation of PGC-1α/NRF/Tfam Pathway.

Uranyl acetate (UA)-induced renal injury disrupts mitochondrial ultrastructure and homeostasis through oxidative stress-mediated pathways, with activating transcription factor 4 (ATF4) identified as a critical molecular switch. This study demonstrates ATF4 directly suppresses peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) transcription via promoter binding, as validated by chromatin immunoprecipitation and luciferase reporter assays. Integrated bioinformatics of renal injury datasets (GSE34351, GSE87024) revealed co-expression networks converging on mitochondrial regulators. In UA-exposed mice, ATF4 silencing rescued mitochondrial biogenesis by activating PGC-1α, restoring cristae architecture observed by transmission electron microscopy and upregulating biogenesis markers (NRF1, Tfam, CPS1). Adipose-derived stem cell exosomes (ADSC-exo) were isolated as biological mediators that attenuated renal uranium accumulation, serum oxidative stress, and histopathological damage. Mechanistically, ADSC-exo inhibited ATF4 to unleash PGC-1α-driven mitochondrial biogenesis, thereby reestablishing redox homeostasis. These findings support the ATF4/PGC-1α axis as an important regulatory pathway involved in mitochondrial impairment during uranium nephrotoxicity.