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• PM 2.5 triggers mitochondrial morphological and function damage of H9c2 cells. • MiR-421/SIRT3 pathway regulates cardiac mitochondrial dynamics imbalance after PM 2.5 treatment. • MiR-421 inhibitor and resveratrol protect PM 2.5 -induced mitochondrial damage. Fine particulate matter (PM 2.5) exposure is associated with cardiovascular disease (CVD) morbidity and mortality. Mitochondria are sensitive targets of PM 2.5 , and mitochondrial dysfunction is closely related to the occurrence of CVD. The epigenetic mechanism of PM 2.5 -triggered mitochondrial injury of cardiomyocytes is unclear. This study focused on the miR-421/SIRT3 signaling pathway to investigate the regulatory mechanism in cardiac mitochondrial dynamics imbalance in rat H9c2 cells induced by PM 2.5. Results illustrated that PM 2.5 impaired mitochondrial function and caused dynamics homeostasis imbalance. Besides, PM 2.5 up-regulated miR-421 and down-regulated SIRT3 gene expression, along with decreasing p-FOXO3a (SIRT3 downstream target gene) and p-Parkin expression and triggering abnormal expression of fusion gene OPA1 and fission gene Drp1. Further, miR-421 inhibitor (miR-421i) and resveratrol significantly elevated the SIRT3 levels in H9c2 cells after PM 2.5 exposure and mediated the expression of SOD2, OPA1 and Drp1, restoring the mitochondrial morphology and function. It suggests that miR-421/SIRT3 pathway plays an epigenetic regulatory role in mitochondrial damage induced by PM 2.5 and that miR-421i and resveratrol exert protective effects against PM 2.5 -incurred cardiotoxicity. [Display omitted] [ABSTRACT FROM AUTHOR]