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

• Autorzy: Lei Q. , Tan J. , Yi S. , Wu N. , Wang Y. , Wu H.
• Języki publikacji: EN

Abstrakty

EN

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

• Wydawca: -
• Czasopismo: Cellular and Molecular Biology Letters
• Rocznik: 2018
• Tom: 23
• Opis fizyczny: p.1-16,fig.,ref.

Twórcy

autor

Lei Q.

• Department of Neurology, First Hospital Affiliated to University of South China, Hunan, China

autor

Tan J.

• Department of Neurology, First Hospital Affiliated to University of South China, Hunan, China

autor

Yi S.

• Department of Neurology, First Hospital Affiliated to University of South China, Hunan, China

autor

Wu N.

• Department of Neurology, First Hospital Affiliated to University of South China, Hunan, China

autor

Wang Y.

• Department of Neurology, First Hospital Affiliated to University of South China, Hunan, China

autor

Wu H.

• Department of Neurology, First Hospital Affiliated to University of South China, Hunan, Chinap.

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Identyfikatory

DOI

10.1186/s11658-018-0081-5