Gestational exposure to PM_2.5 impaired cardiac development through ANGPTL4-mediated mitochondrial metabolic...

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.