Flower-Like Molybdenum Disulfide Nanostructures for Promoting Mitochondrial Homeostasis and Attenuating Inflammatory Endothelial Dysfunction

Mitochondrial dynamics is crucial to cellular metabolic homeostasis, development, and remodeling. However, the perturbation of mitochondrial dynamics impairs endothelial functions, leading to numerous diseases, including cardiovascular diseases. The few-layered molybdenum disulfide (MoS2)-based nanoagents hold great potential as therapeutic agents for various disorders. Herein, we investigated whether flower-like MoS2 nanosheets (FL-MoS2) promote mitochondrial homeostasis via modulating mitochondrial dynamics in endothelial cells. Our results demonstrated that mitochondrial elements become dramatically elongated in endothelial cells in response to FL-MoS2, suggesting that FL-MoS2 promotes mitochondrial fusion rather than fission. The molecular mechanisms mediating mitochondrial fusion by FL-MoS2 involved the upregulation of pro-fusion proteins as well as a decrease in mitochondrial translocation of dynamin-related protein 1 (Drp1). Consistently, we demonstrated that FL-MoS2 maintains mitochondrial homeostasis through regulating transcription factor EB (TFEB)-mediated mitochondrial dynamics and biogenesis. In addition, we established that mitochondrial tubulation in response to FL-MoS2 protects endothelial cells from mitochondrial impairments induced by tumor necrosis factor (TNF) α. Our results revealed the unique ability of MoS2-based nanoagents to modulate mitochondrial homeostasis, contributing to improvements in endothelial functions.