Melatonin alleviates palmitic acid-induced mitochondrial dysfunction by reducing oxidative stress and enhancing autophagy in bovine endometrial epithelial cells.

IF 6.3 Q1 AGRICULTURE, DAIRY & ANIMAL SCIENCE
Yi Wang, Jianfei Gong, Nuo Heng, Yingfan Hu, Rui Wang, Huan Wang, Wei He, Ni Zhu, Zhihui Hu, Haisheng Hao, Huabin Zhu, Shanjiang Zhao
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Abstract

Background: Negative energy balance (NEB) typically occurs in dairy cows after delivery. Cows with a high yield are more likely to experience significant NEB. This type of metabolic imbalance could cause ketosis, which is often accompanied by a decline in reproductive performance. However, the molecular mechanisms underlying NEB have yet to be fully elucidated. During excessive NEB, the body fat is extensively broken down, resulting in the abnormal accumulation of non-esterified fatty acids (NEFAs), represented by palmitic acid (PA), within the uterus. Such an abnormal accumulation has the potential to damage bovine endometrial epithelial cells (BEECs), while the molecular mechanisms underlying its involvement in the PA-induced injury of BEECs remains poorly understood. Melatonin (MT) is recognized for its regulatory role in maintaining the homeostasis of mitochondrial reactive oxygen species (mitoROS). However, little is known as to whether MT could ameliorate the damage incurred by BEECs in response to PA and the molecular mechanism involved.

Results: Analysis showed that 0.2 mmol/L PA stress increased the level of cellular and mitochondrial oxidative stress, as indicated by increased reactive oxygen species (ROS) level. In addition, we observed mitochondrial dysfunction, including abnormal mitochondrial structure and respiratory function, along with a reduction in mitochondrial membrane potential and mitochondrial copy number, and the induction of apoptosis. Notably, we also observed the upregulation of autophagy proteins (PINK, Parkin, LC3B and Ubiquitin), however, the P62 protein was also increased. As we expected, 100 μmol/L of MT pre-treatment attenuated PA-induced mitochondrial ROS and restored mitochondrial respiratory function. Meanwhile, MT pretreatment reversed the upregulation of P62 induced by PA and activated the AMPK-mTOR-Beclin-1 pathway, contributing to an increase of autophagy and decline apoptosis.

Conclusions: Our findings indicate that PA can induce mitochondrial dysfunction and enhance autophagy in BEECs. In addition, MT is proved to not only reduce mitochondrial oxidative stress but also facilitate the clearance of damaged mitochondria by upregulating autophagy pathways, thereby safeguarding the mitochondrial pool and promoting cellular viability. Our study provides a better understanding of the molecular mechanisms underlying the effect of an excess of NEB on the fertility outcomes of high yielding dairy cows.

褪黑素通过减少氧化应激和增强牛子宫内膜上皮细胞的自噬作用,缓解棕榈酸诱导的线粒体功能障碍。
背景:负能量平衡(NEB)通常发生在分娩后的奶牛身上。高产奶牛更容易出现明显的负能量平衡。这种类型的代谢失衡可能导致酮病,而酮病往往伴随着繁殖性能的下降。然而,NEB 的分子机制尚未完全阐明。在过度 NEB 期间,体内脂肪被大量分解,导致以棕榈酸(PA)为代表的非酯化脂肪酸(NEFAs)在子宫内异常积累。这种异常积累有可能对牛子宫内膜上皮细胞(BEECs)造成损伤,但其参与 PA 诱导的 BEECs 损伤的分子机制仍鲜为人知。褪黑素(MT)在维持线粒体活性氧(mitoROS)平衡方面的调节作用已得到公认。然而,人们对 MT 能否改善 BEECs 对 PA 的损伤及其分子机制知之甚少:分析表明,0.2 毫摩尔/升 PA 应激增加了细胞和线粒体的氧化应激水平,表现为活性氧(ROS)水平升高。此外,我们还观察到线粒体功能障碍,包括线粒体结构和呼吸功能异常、线粒体膜电位和线粒体拷贝数降低以及诱导细胞凋亡。值得注意的是,我们还观察到自噬蛋白(PINK、Parkin、LC3B 和泛素)的上调,但 P62 蛋白也有所增加。正如我们所预期的那样,100 μmol/L MT 预处理可减轻 PA 诱导的线粒体 ROS 并恢复线粒体呼吸功能。同时,MT预处理逆转了PA诱导的P62上调,激活了AMPK-mTOR-Beclin-1通路,有助于增加自噬和减少细胞凋亡:我们的研究结果表明,PA 可诱导 BEECs 线粒体功能障碍并增强自噬。结论:我们的研究结果表明,PA 可诱导 BEECs 线粒体功能障碍并增强其自噬功能。此外,MT 不仅能降低线粒体氧化应激,还能通过上调自噬途径促进受损线粒体的清除,从而保护线粒体池并提高细胞活力。我们的研究让人们更好地了解了过量 NEB 对高产奶牛生育结果影响的分子机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
10.30
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