Mitochondrial Fission Mediates Endothelial Inflammation

Abstract

Endothelial inflammation and mitochondrial dysfunction have been implicated in cardiovascular diseases, yet, a unifying mechanism tying them together remains limited. Mitochondrial dysfunction is frequently associated with mitochondrial fission/fragmentation mediated by the GTPase Drp1 (dynamin-related protein 1). Nuclear factor (NF)-κB, a master regulator of inflammation, is implicated in endothelial dysfunction and resultant complications. Here, we explore a causal relationship between mitochondrial fission and NF-κB activation in endothelial inflammatory responses. In cultured endothelial cells, TNF-α (tumor necrosis factor-α) or lipopolysaccharide induces mitochondrial fragmentation. Inhibition of Drp1 activity or expression suppresses mitochondrial fission, NF-κB activation, vascular cell adhesion molecule-1 induction, and leukocyte adhesion induced by these proinflammatory factors. Moreover, attenuations of inflammatory leukocyte adhesion were observed in Drp1 heterodeficient mice as well as endothelial Drp1 silenced mice. Intriguingly, inhibition of the canonical NF-κB signaling suppresses endothelial mitochondrial fission. Mechanistically, NF-κB p65/RelA seems to mediate inflammatory mitochondrial fission in endothelial cells. In addition, the classical anti-inflammatory drug, salicylate, seems to maintain mitochondrial fission/fusion balance against TNF-α via inhibition of NF-κB. In conclusion, our results suggest a previously unknown mechanism whereby the canonical NF-κB cascade and a mitochondrial fission pathway interdependently regulate endothelial inflammation.

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

“…Mitochondria, a highly dynamic organelle that is primarily responsible for generating the main source of ATP, also participated in fundamental cellular functions, including survival, apoptosis, redox status, and signaling responses to environmental stimuli. − An impaired balance of mitochondrial dynamics, primarily a shift toward fission, has been associated with disturbed cellular physiology, resulting in a variety of diseases including cardiovascular diseases. , In this study, FL-MoS 2 predisposed a shift toward mitochondrial fusion rather than fission in endothelial cells, which was indicated by an increase in the tubular form of mitochondria, accompanied by the elevated expression of mitochondrial fusion proteins (Mfn2, Opa1), as well as the decreased expression fission proteins (Fis1) in FL-MoS 2 -treated HUVECs. Furthermore, as an early signaling event response to FL-MoS 2 , an increase in S637 phosphorylation accompanied by a decreased in S616 phosphorylation of Drp1 were observed in FL-MoS 2 -treated HUVECs, which resulted in a decreased Drp1 recruitment to mitochondria.…”

“…7−9 Accumulating evidence suggests that abnormal mitochondrial dynamics directly affect mitochondrial functions, which could generate excessive reactive oxygen species (ROS), impair bioenergetics, elicit aberrant mitophagy, and ultimately programmed cell death. 9,10 Endothelial dysfunction as a characteristic of the aging process is a well-clarified risk factor of cardiovascular diseases, such as coronary artery diseases and hypertension. 11,12 Oxidative stress and inflammation are the major contributing factors to endothelial dysfunction.…”

“…In contrast, dynamin 1-like (Drp1) and fission protein 1 (Fis1) participate in regulating mitochondrial fission . This balance of mitochondrial dynamics is highly sensitive to various stresses, such as bioenergetic dysfunctions, hypoxia, high glucose, and oxidative stress. − Accumulating evidence suggests that abnormal mitochondrial dynamics directly affect mitochondrial functions, which could generate excessive reactive oxygen species (ROS), impair bioenergetics, elicit aberrant mitophagy, and ultimately programmed cell death. , …”

Altered Mitochondrial Opa1-Related Fusion in Mouse Promotes Endothelial Cell Dysfunction and Atherosclerosis

“…The mitochondrial shape was analyzed using the Image J—Fiji software (version: 2.1.0/1.53c) as previously described [ 43 , 44 ] on the endothelial cells stained as described above. Images were acquired using Metamorph software and imported into ImageJ.…”

“…The mitochondrial fission count (MFC) was then measured as it represents the mitochondria dynamics. MFC was calculated as the total number of mitochondria in a cell divided by the mitochondrial area in the same cell [ 44 ].…”