Journal
JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY
Volume 35, Issue 5, Pages -Publisher
WILEY
DOI: 10.1002/jbt.22737
Keywords
calcium; endothelial cells; homocysteine; mitochondria‐ associated membranes; mitochondrial dysfunction
Categories
Funding
- National Key R&D Program of China [2017YFE0102200]
- Public Welfare Project of Zhejiang Provincial Science and Technology Department [LGF21H310005]
- National Natural Sciences Foundation of China [81573426]
- Zhejiang Provincial Natural Science Foundation of China [LQ16H310003]
Ask authors/readers for more resources
Homocysteine-induced mitochondrial dysfunction and dynamics disorder in endothelial cells are mainly related to the increase of calcium due to the upregulation of the MCU and the IP3R-Grp75-VDAC complex in MAMs.
Homocysteine (Hcy) is a sulfur-containing amino acid that originated in methionine metabolism and the elevated level of Hcy in plasma is considered to be an independent risk factor for cardiovascular diseases (CVD). Endothelial dysfunction plays a major role in the development of CVD, while the potential mechanism of Hcy-induced endothelial dysfunction is still unclear. Here, in Hcy-treated endothelial cells, we observed the destruction of mitochondrial morphology and the decline of mitochondrial membrane potential. Meanwhile, the level of ATP was reduced and the reactive oxygen species was increased. The expressions of dynamin-related protein 1 (Drp1) and phosphate-Drp1 (Ser616) were upregulated, whereas the expression of mitofusin 2 was inhibited by Hcy treatment. These findings suggested that Hcy not only triggered mitochondrial dysfunction but also incurred an imbalance of mitochondrial dynamics in endothelial cells. The expression of mitochondrial calcium uniporter (MCU) was activated by Hcy, contributing to calcium transferring into mitochondria. Interestingly, the formation of mitochondria-associated membranes (MAMs) was increased in endothelial cells after Hcy administration. The inositol 1,4,5-triphosphate receptor (IP3R)-glucose-regulated protein 75 (Grp75)-voltage-dependent anion channel (VDAC) complex, which was enriched in MAMs, was also increased. The accumulation of mitochondrial calcium could be blocked by inhibiting with the IP3R inhibitor Xestospongin C (XeC) in Hcy-treated cells. Then, we confirmed that the mitochondrial dysfunction and the increased mitochondrial fission induced by Hcy could be attenuated after Hcy and XeC co-treatment. In conclusion, Hcy-induced mitochondrial dysfunction and dynamics disorder in endothelial cells were mainly related to the increase of calcium as a result of the upregulated expressions of the MCU and the IP3R-Grp75-VDAC complex in MAMs.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available