Mitochonic acid 5 activates the MAPK-ERK-yap signaling pathways to protect mouse microglial BV-2 cells against TNFα-induced apoptosis via increased Bnip3-related mitophagy.
Mitochonic acid 5 activates the MAPK-ERK-yap signaling pathways to protect mouse microglial BV-2 cells against TNFα-induced apoptosis via increased Bnip3-related mitophagy.
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DOI：
10.1186/s11658-018-0081-5
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发表时间：
2018
影响因子：
8.3
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Lei Q;Tan J;Yi S;Wu N;Wang Y;Wu H
通过线粒体稳态调节小胶质细胞功能在神经炎症的发展中很重要。这种调节功能的基本机制仍不清楚。在本研究中，我们研究了线粒体酸 5 (MA-5) 在 TNFα 诱导的炎症损伤后小胶质细胞线粒体凋亡中的保护作用。 TNFα 用于诱导小鼠小胶质细胞 BV-2 细胞的炎症损伤，无论是否经过 MA-5 处理。使用 MTT 和 TUNEL 测定评估细胞凋亡。通过线粒体膜电位 JC-1 染色、ROS 流式细胞术分析、mPTP 开放评估和 cyt-c 免疫荧光评估线粒体功能。使用蛋白质印迹和免疫荧光检查线粒体自噬。使用蛋白质印迹和带有途径阻断剂的免疫荧光进行途径分析。我们的结果表明，TNFα 通过激活 caspase-9 依赖性线粒体凋亡途径诱导小胶质细胞 BV-2 细胞系凋亡。从机制上讲，炎症降低了线粒体电位，诱导ROS产生，并导致线粒体促凋亡因子渗漏到细胞质中。炎症反应降低了细胞能量代谢并增加了氧化应激。相比之下，MA-5 治疗通过上调线粒体自噬减少线粒体凋亡。线粒体自噬的增加会降解受损的线粒体，破坏线粒体凋亡，中和 ROS 过量产生，并改善细胞能量产生。我们还发现 MA-5 通过 Bnip3 通过 MAPK-ERK-Yap 信号通路调节线粒体自噬。抑制该信号通路或敲低 Bnip3 表达可阻止 MA-5 对线粒体稳态和增加小胶质细胞凋亡产生有益影响。 TNFα 诱导的炎症损伤后，MA-5 通过放大保护性 Bnip3 相关线粒体自噬（通过 MAPK-ERK-Yap 信号通路介导）来影响小胶质细胞线粒体稳态。
The regulation of microglial function via mitochondrial homeostasis is important in the development of neuroinflammation. The underlying mechanism for this regulatory function remains unclear. In this study, we investigated the protective role of mitochonic acid 5 (MA-5) in microglial mitochondrial apoptosis following TNFα-induced inflammatory injury. TNFα was used to induce inflammatory injury in mouse microglial BV-2 cells with and without prior MA-5 treatment. Cellular apoptosis was assessed using the MTT and TUNEL assays. Mitochondrial functions were evaluated via mitochondrial membrane potential JC-1 staining, ROS flow cytometry analysis, mPTP opening assessment, and immunofluorescence of cyt-c. Mitophagy was examined using western blots and immunofluorescence. The pathways analysis was carried out using western blots and immunofluorescence with a pathway blocker. Our results demonstrated that TNFα induced apoptosis in the microglial BV-2 cell line by activating the caspase-9-dependent mitochondrial apoptotic pathway. Mechanistically, inflammation reduced mitochondrial potential, induced ROS production, and contributed to the leakage of mitochondrial pro-apoptotic factors into the cytoplasm. The inflammatory response reduced cellular energy metabolism and increased oxidative stress. By contrast, treatment with MA-5 reduced mitochondrial apoptosis via upregulation of mitophagy. Increased mitophagy degraded damaged mitochondria, disrupting mitochondrial apoptosis, neutralizing ROS overproduction, and improving cellular energy production. We also identified that MA-5 regulated mitophagy via Bnip3 through the MAPK–ERK–Yap signaling pathway. Inhibiting this signaling pathway or knocking down Bnip3 expression prevented MA-5 from having beneficial effects on mitochondrial homeostasis and increased microglial apoptosis. After TNFα-induced inflammatory injury, MA-5 affects microglial mitochondrial homeostasis in a manner mediated via the amplification of protective, Bnip3-related mitophagy, which is mediated via the MAPK–ERK–Yap signaling pathway.
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影响因子：
3.6
作者：
Wen Y;Ji Y;Zhang Y;Jiang B;Tang C;Wang Q;Chen X;Jia L;Gu W;Xu X
通讯作者：
Xu X
影响因子：
--
作者：
Chuang KA;Li MH;Lin NH;Chang CH;Lu IH;Pan IH;Takahashi T;Perng MD;Wen SF
通讯作者：
Wen SF
影响因子：
82.9
作者：
Rothhammer V;Mascanfroni ID;Bunse L;Takenaka MC;Kenison JE;Mayo L;Chao CC;Patel B;Yan R;Blain M;Alvarez JI;Kébir H;Anandasabapathy N;Izquierdo G;Jung S;Obholzer N;Pochet N;Clish CB;Prinz M;Prat A;Antel J;Quintana FJ
通讯作者：
Quintana FJ
影响因子：
4.8
作者：
Perdiz, Daniel;Lorin, Severine;Pous, Christian
通讯作者：
Pous, Christian
影响因子：
12.4
作者：
Van Nostrand, Jeanine L.;Bowen, Margot E.;Attardi, Laura D.
通讯作者：
Attardi, Laura D.