PM_2.5 induces cardiac defects via AHR-SIRT1-PGC-1α mediated mitochondrial damage

Recent evidence indicates that PM_2.5 poses a risk for congenital heart diseases_, but the mechanisms remain unclear. We hypothesized that AHR activated by PM_2.5 might cause mitochondrial damage via PGC-1α dysregulation, leading to heart defects. We initially discovered that the PGC-1α activator ZLN005 counteracted cardiac defects in zebrafish larvae exposed to EOM (extractable organic matter) from PM_2.5. Moreover, ZLN005 attenuated EOM-induced PGC-1α downregulation, mitochondrial dysfunction/biogenesis, and apoptosis. EOM exposure not only decreased PGC-1α expression levels, but suppressed its activity via deacetylation, and SIRT1 activity is required during both processes. We then found that SIRT1 expression levels and NAD⁺/NADH ratio were reduced in an AHR-dependent way. We also demonstrated that AHR directly suppressed the transcription of SIRT1 while promoted the transcription of TiPARP which consumed NAD⁺. In conclusion, our study suggests that PM_2.5 induces mitochondrial damage and heart defects via AHR/SIRT1/PGC-1α signal pathway.