Melatonin Represses Mitophagy to Protect Mouse Granulosa Cells from Oxidative Damage.
Melatonin Represses Mitophagy to Protect Mouse Granulosa Cells from Oxidative Damage.
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DOI：
10.3390/biom11070968
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发表时间：
2021-06-30
期刊：
影响因子：
5.5
通讯作者：
Liu H
中科院分区：
文献类型：
--
作者：
Jiang Y;Shen M;Chen Y;Wei Y;Tao J;Liu H
各种环境刺激，包括氧化应激，可导致颗粒细胞（GC）死亡通过线粒体自噬。近年来，研究发现褪黑素（MEL）对氧化损伤后胃癌的存活有重要影响。在这里，我们发现MEL抑制氧化应激诱导的线粒体自噬，以促进GC的生存。MEL处理后，H2O2暴露后细胞活力的损失显着恢复。同时，MEL抑制氧化应激过程中线粒体自噬的激活。值得注意的是，阻断线粒体自噬抑制氧化应激引起的GC死亡。然而，MEL不能进一步恢复用线粒体自噬抑制剂处理的细胞的活力。此外，PTEN诱导的推定激酶1（PINK1），线粒体丝氨酸/苏氨酸蛋白激酶，在氧化应激过程中被MEL抑制。结果，E3连接酶帕金未能转移到线粒体，导致线粒体清除受损。使用RNAi敲低PINK1表达，我们进一步验证了MEL-PINK1-Parkin（MPP）通路通过抑制线粒体自噬在维持GC存活中的作用。我们的研究结果不仅阐明了MEL对GC氧化损伤的保护机制，而且还扩展了对昼夜节律如何影响卵巢卵泡发育的理解。这些发现揭示了褪黑素通过抑制线粒体自噬来防御GC氧化损伤的新机制，这可能是无排卵疾病的潜在治疗靶点。
Various environmental stimuli, including oxidative stress, could lead to granulosa cell (GC) death through mitophagy. Recently, it was reported that melatonin (MEL) has a significant effect on GC survival during oxidative damage. Here, we found that MEL inhibited oxidative stress-induced mitophagy to promote GC survival. The loss of cell viability upon H2O2 exposure was significantly restored after MEL treatment. Concomitantly, MEL inhibited the activation of mitophagy during oxidative stress. Notably, blocking mitophagy repressed GC death caused by oxidative stress. However, MEL cannot further restore viability of cells treated with mitophagy inhibitor. Moreover, PTEN-induced putative kinase 1 (PINK1), a mitochondrial serine/threonine-protein kinase, was inhibited by MEL during oxidative stress. As a result, the E3 ligase Parkin failed to translocate to mitochondria, leading to impaired mitochondria clearance. Using RNAi to knock down PINK1 expression, we further verified the role of the MEL-PINK1-Parkin (MPP) pathway in maintaining GC survival by suppressing mitophagy. Our findings not only clarify the protective mechanisms of MEL against oxidative damage in GCs, but also extend the understanding about how circadian rhythms might influence follicles development in the ovary. These findings reveal a new mechanism of melatonin in defense against oxidative damage to GCs by repressing mitophagy, which may be a potential therapeutic target for anovulatory disorders.
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