Sirtuin 3 regulation:a target to alleviateβ-hydroxybutyric acid-induced mitochondrial dysfunction in bovine granulosa cells

作     者：Shanjiang Zhao Jianfei Gong Yi Wang Nuo Heng Huan Wang Zhihui Hu Haoyu Wang Haobo Zhang Huabin Zhu Shanjiang Zhao;Jianfei Gong;Yi Wang;Nuo Heng;Huan Wang;Zhihui Hu;Haoyu Wang;Haobo Zhang;Huabin Zhu

作者机构：State Key Laboratory of Animal NutritionKey Laboratory of Animal GeneticsBreeding and Reproduction of Ministry of Agriculture and Rural AffairsInstitute of Animal ScienceChinese Academy of Agricultural SciencesBeijingChina 

出 版 物：《Journal of Animal Science and Biotechnology》 (畜牧与生物技术杂志（英文版）)

年 卷 期：2023年第14卷第4期

页      面：1377-1394页

核心收录：

学科分类：0905[农学-畜牧学] 09[农学] 

基　　金：supported by the National Natural Science Foundation of China(32102549) the National Key R&D Program of Ningxia(2021BEF02023) the earmarked fund for CARS(CARS-36) the Agricultural Science and Technology Innovation Program(ASTIP-IAS06) the National Key R&D Program of Gansu(21YF5NJ196)。 

主　　题：BHBA Dairy cows Granulosa cells Ketosis Mitochondrial function Sirt3 

摘      要：Background 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 byβ-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.Results 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 Ca^(2+)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.Conclusions 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.