Mitochondrial metabolism reprogramming-mediated cardiomyocyte senescence involved in arsenic stress-evoked heart failure

Abstract

Chronic exposure to environmental inorganic arsenic is associated with cardiotoxicity, but the underlying mechanisms remain poorly understood. This study investigated how arsenite disrupts mitochondrial metabolism, focusing on the tricarboxylic acid (TCA) cycle, and its role in cardiomyocyte senescence and dysfunction. Proteomics and metabolomics analysis revealed that environmental arsenic exposure altered mitochondrial electron transport chain (ETC) proteins and impaired key enzymes in the TCA cycle, including citrate synthase and succinate dehydrogenase. In vivo drinking exposure to environmental arsenite for six months significantly downregulated mitochondrial metabolic enzymes, leading to disruptions in energy metabolism and cardiac aging. In vitro experiments using AC16 human cardiomyocytes confirmed that environmental arsenite exposure induced early senescence, characterized by increased expression of the aging-related marker CDKN1A and the cardiac injury marker NPPB. Even sub-cytotoxic doses of arsenite impaired mitochondrial TCA cycle function before inducing senescence and injury. Dietary supplementation with nicotinamide mononucleotide (NMN) in vivo and administration with NMN in vitro mitigated cardiomyocyte senescence-associated secretory phenotype and heart failure, suggesting that cardiac aging plays a central role in arsenic-induced functional impairment. Treatment with the mitochondrial antioxidant Mito-TEMPO alleviated these effects, restoring TCA cycle enzyme activity, reducing senescence, and improving cardiomyocyte function across multiple cell generations. These findings suggest that mitochondrial metabolic reprogramming plays a central role in environmental stressor arsenite-induced cardiomyocyte aging and identify mitochondrial metabolism as a potential target to mitigate arsenic-induced cardiac dysfunction.