1. Academic Validation
  2. PM2.5 induces cardiac defects via AHR-SIRT1-PGC-1α mediated mitochondrial damage

PM2.5 induces cardiac defects via AHR-SIRT1-PGC-1α mediated mitochondrial damage

  • Environ Toxicol Pharmacol. 2024 Feb 15:106:104393. doi: 10.1016/j.etap.2024.104393.
Jin Chen 1 Mingxuan Zhang 1 Stanley Aniagu 2 Yan Jiang 3 Tao Chen 4
Affiliations

Affiliations

  • 1 Suzhou medical college, Soochow University, Suzhou, China; MOE Education Key Laboratory of Geriatric Diseases and Immunology, Suzhou, China.
  • 2 Toxicology, Risk Assessment, and Research Division, Texas Commission on Environmental Quality, 12015 Park 35 Cir, Austin TX, USA.
  • 3 Suzhou medical college, Soochow University, Suzhou, China. Electronic address: yjiang@suda.edu.cn.
  • 4 Suzhou medical college, Soochow University, Suzhou, China; MOE Education Key Laboratory of Geriatric Diseases and Immunology, Suzhou, China. Electronic address: tchen@suda.edu.cn.
Abstract

Recent evidence indicates that PM2.5 poses a risk for congenital heart diseases, but the mechanisms remain unclear. We hypothesized that AHR activated by PM2.5 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 PM2.5. 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 PM2.5 induces mitochondrial damage and heart defects via AHR/SIRT1/PGC-1α signal pathway.

Keywords

AHR; Heart development; Mitochondria; PGC-1α; PM(2.5); SIRT1.

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