Work

Gestational exposure to PM2.5 impaired cardiac development through ANGPTL4-mediated mitochondrial metabolic dysfunction

Year: 2025

Type: article

Abstract: • ANGPTL4 and SIRT3 are potential biomarkers for air pollution-related CHD. • Maternal PM 2.5 exposure impaired cardiac function in offsprings. • PM 2.5 upregulated ANGPTL4 to inhibit SITR3 in cardiomyocytes. • Reduced SIRT3 by PM 2.5 increased acetylation of LONP1. • PM 2.5 suppressed D2HGDH to block the conversion of D2-HG to α-KG. Increasing epidemiological studies suggested that maternal exposure to fine particulate matter (PM 2.5 ) was associated with congenital heart defects (CHD) in fetuses, while the exact mechanisms were still unclear. This study aimed to investigate PM 2.5 -induced effects on cardiac development and elucidate the implicated mechanisms. In the present study, we first identified that angiopoietin-like 4 (ANGPTL4), sirtuin 3 (SIRT3), and D2-hydroxyglutarate (D2-HG) may be potential biomarkers for PM 2.5 -related cardiac defects in human umbilical cord serum samples. Moreover, in utero exposure to PM 2.5 resulted in increased left ventricular wall thickness, mitochondrial dysfunction, and metabolic changes in the hearts of the offspring mice, while knockout of ANGPTL4 could attenuate PM 2.5 -induced pathological changes. Furthermore, in vitro investigations revealed that ANGPTL4 may directly bind to a mitochondria-located deacetylase SIRT3 and inhibit its deacetylation capacity. Reduced SIRT3 subsequently enhanced the acetylation of lon peptidase 1 (LONP1), a quality-control protease that was indispensable in maintaining mitochondrial function. More importantly, mitochondrial dysfunction caused by loss of LONP1 further reduced the expression of D2-hydroxyglutarate dehydrogenase (D2HGDH), which disrupted the conversion of D2HG to α-ketoglutarate (α-KG) and impeded energy generation in mitochondria. These findings suggested that PM 2.5 may impair cardiac development through ANGPTL4-mediated mitochondrial dysfunction, which provided a mechanistic basis for further investigation and prevention of PM 2.5 -related birth defects.

Source: Journal of Advanced Research

DOI: 10.1016/j.jare.2025.11.022