Sirtuin 3 regulation: a target to alleviate β-hydroxybutyric acid-induced mitochondrial dysfunction in bovine granulosa cells.
Sirtuin 3 regulation: a target to alleviate β-hydroxybutyric acid-induced mitochondrial dysfunction in bovine granulosa cells.
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DOI：
10.1186/s40104-022-00825-w
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发表时间：
2023-02-14
影响因子：
7
通讯作者：
Zhu, Huabin
中科院分区：
文献类型：
--
作者：
Zhao, Shanjiang;Gong, Jianfei;Wang, Yi;Heng, Nuo;Wang, Huan;Hu, Zhihui;Wang, Haoyu;Zhang, Haobo;Zhu, Huabin
在这一过渡时期，由于干物质摄入不足，大量产奶所需能量消耗急剧增加，高产奶牛进入能量负平衡，酮体增加，繁殖效率下降。以β-羟基丁酸（BHBA）为代表的过量浓度的循环KB可导致氧化损伤，这可能导致卵泡颗粒细胞（fGC）损伤和卵泡发育延迟。Sirtuin 3（Sirt 3）以有益的方式调节线粒体活性氧（mitoROS）稳态;然而，其参与BHBA诱导的fGC损伤的分子机制知之甚少。本研究旨在探讨Sirt 3对BHBA过负荷致fGCs损伤的保护作用及其机制。我们的研究结果表明，2.4 mmol/L的BHBA应激增加了牛fGC中的mitoROS水平。进一步的研究确定了随后的线粒体功能障碍，包括线粒体结构异常率增加、线粒体通透性转换孔（MPTP）开放、线粒体膜电位（MMP）和Ca 2+释放降低;这些功能障碍然后触发fGC中凋亡的半胱天冬酶级联反应。值得注意的是，治疗前Sirt 3的过表达通过增加Beclin-1的表达水平来增强线粒体自噬，从而防止fGC中BHBA诱导的线粒体氧化应激和线粒体功能障碍。此外，我们的数据表明，AMPK-mTOR-Beclin-1通路可能参与Sirt 3对BHBA刺激引发的细胞损伤的保护机制。这些发现表明，Sirt 3通过增强自噬、减轻氧化应激和线粒体损伤来保护fGC免受BHBA触发的损伤。本研究为减轻酮病奶牛过度BHBA应激引起的fGCs损伤提供了新的策略。在线版本包含补充材料，可通过10.1186/s40104-022-00825-w获得。
During the transition period, the insufficient dry matter intake and a sharply increased in energy consumption to produce large quantities of milk, high yielding cows would enter a negative energy balance (NEB) that causes an increase in ketone bodies (KBs) and decrease in reproduction efficiency. The excess concentrations of circulating KBs, represented by β-hydroxybutyric acid (BHBA), could lead to oxidative damage, which potentially cause injury to follicular granulosa cells (fGCs) and delayed follicular development. Sirtuin 3 (Sirt3) regulates mitochondria reactive oxygen species (mitoROS) homeostasis in a beneficial manner; however, the molecular mechanisms underlying its involvement in the BHBA-induced injury of fGCs is poorly understood. The aim of this study was to explore the protection effects and underlying mechanisms of Sirt3 against BHBA overload-induced damage of fGCs. Our findings demonstrated that 2.4 mmol/L of BHBA stress increased the levels of mitoROS in bovine fGCs. Further investigations identified the subsequent mitochondrial dysfunction, including an increased abnormal rate of mitochondrial architecture, mitochondrial permeability transition pore (MPTP) opening, reductions in mitochondrial membrane potential (MMP) and Ca2+ release; these dysfunctions then triggered the caspase cascade reaction of apoptosis in fGCs. Notably, the overexpression of Sirt3 prior to treatment enhanced mitochondrial autophagy by increasing the expression levels of Beclin-1, thus preventing BHBA-induced mitochondrial oxidative stress and mitochondrial dysfunction in fGCs. Furthermore, our data suggested that the AMPK-mTOR-Beclin-1 pathway may be involved in the protective mechanism of Sirt3 against cellular injury triggered by BHBA stimulation. These findings indicate that Sirt3 protects fGCs from BHBA-triggered injury by enhancing autophagy, attenuating oxidative stress and mitochondrial damage. This study provides new strategies to mitigate the fGCs injury caused by excessive BHBA stress in dairy cows with ketosis. The online version contains supplementary material available at 10.1186/s40104-022-00825-w.
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