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首页> 外文期刊>Journal of biochemical and molecular toxicology >Homocysteine induced a calcium-mediated disruption of mitochondrial function and dynamics in endothelial cells
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Homocysteine induced a calcium-mediated disruption of mitochondrial function and dynamics in endothelial cells

机译：同型半胱氨酸诱导内皮细胞中的线粒体功能和动力学的钙介导的破坏

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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.
机译：同型半胱氨酸（Hcy）是一种含硫氨基酸，起源于蛋氨酸代谢，血浆中Hcy水平升高被认为是心血管疾病（CVD）的独立危险因素。内皮功能障碍在CVD的发展中起着重要作用，但同型半胱氨酸诱导内皮功能障碍的潜在机制尚不清楚。在同型半胱氨酸处理的内皮细胞中，我们观察到线粒体形态的破坏和线粒体膜电位的下降。同时，ATP水平降低，活性氧物种增加。动力相关蛋白1（Drp1）和磷酸-Drp1（Ser616）的表达上调，而丝裂原融合蛋白2的表达被Hcy抑制。这些发现表明，同型半胱氨酸不仅引发线粒体功能障碍，而且还导致内皮细胞线粒体动力学失衡。线粒体钙转运蛋白（MCU）的表达被同型半胱氨酸激活，有助于钙转移到线粒体。有趣的是，服用同型半胱氨酸后，内皮细胞中线粒体相关膜（MAM）的形成增加。富含MAMs的肌醇1,4,5-三磷酸受体（IP3R）-葡萄糖调节蛋白75（Grp75）-电压依赖性阴离子通道（VDAC）复合物也增加。IP3R抑制剂Xestospongin C（XeC）可通过抑制同型半胱氨酸处理的细胞中线粒体钙的积累来阻断。然后，我们证实，在Hcy和XeC联合治疗后，Hcy诱导的线粒体功能障碍和线粒体分裂的增加可以减轻。综上所述，同型半胱氨酸诱导的内皮细胞线粒体功能障碍和动力学紊乱主要与MAMs中MCU和IP3R-Grp75-VDAC复合物表达上调导致的钙增加有关。

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