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

Abstract

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.