PM_2.5 exposure impairs mitochondrial function and myocardial contractility in cardiac organoids via the Sirt3/Mdh2...

Ambient fine particulate matter (PM_2.5) is a leading global environmental risk factor for cardiovascular disease. Although PM_2.5 exposure is known to lead to mitochondrial dysfunction, the precise metabolic mechanisms underlying this effect remain incompletely understood. In this study, we investigated the role of the mitochondrial deacetylase Sirt3 in PM_2.5-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiac organoids (hiPSC-COs), a physiologically relevant multicellular model. Our results demonstrated that PM_2.5 exposure compromised the contractile function of COs. Specifically, it induced the expression of myocardial injury markers and triggered a series of mitochondrial impairments, including structural damage, inflammatory response, oxidative stress and loss of membrane potential. Mechanistically, exposure of COs to PM_2.5 suppressed Sirt3 expression, leading to increased acetylation and decreased activity of malate dehydrogenase 2 (Mdh2), a key enzyme in the tricarboxylic acid (TCA) cycle. This disruption resulted in reduced levels of TCA cycle metabolites and a severe ATP deficit. Pharmacological activation of Sirt3 with dihydromyricetin attenuated the PM_2.5-induced mitochondrial dysfunction, restored ATP levels and improved contractility. Our findings elucidate that PM_2.5 impairs cardiac energy metabolism via the Sirt3/Mdh2 pathway, identifying Sirt3 as a potential therapeutic target for mitigating PM_2.5-related cardiovascular dysfunction.