Sirtuin 3 attenuates neuroinflammation-induced apoptosis in BV-2 microglia

Aging (Albany NY). 2019 Oct 20;11(20):9075-9089. doi: 10.18632/aging.102375. Epub 2019 Oct 20.

Abstract

In this study, we explored the upstream regulatory mechanisms underlying inflammation-induced mitochondrial dysfunction in microglial BV-2 cells. Our results demonstrate that Sirtuin 3 (Sirt3) expression was downregulated in response to LPS-induced neuroinflammation. In addition, overexpression of Sirt3 attenuated LPS-induced BV-2 cell death. Functional studies illustrated that Sirt3 overexpression promoted normal mitochondrial function and inhibited mitochondria-dependent apoptosis in LPS-treated BV-2 cells. At the molecular level, suppressor of ras val-2 (SRV2) promoted LPS-mediated mitochondrial damage by inducing mitochondrial fission. Sirt3 overexpression, which suppressed the transcription of SRV2 and thus suppressed mitochondrial fission, played an anti-apoptotic role in LPS-treated BV-2 cells. Furthermore, Sirt3 inhibited SRV2 expression via the Mst1-JNK pathway, and re-activation of this pathway abolished the protective effects of Sirt3 on mitochondrial damage and apoptosis. Taken together, our results indicate that Sirt3-induced, Mst1-JNK-SRV2 signaling pathway-dependent inhibition of mitochondrial fission protected against neuroinflammation-mediated cell damage in BV-2 microglia. Sirt3 might therefore be an effective treatment for neuroinflammation.

Keywords: Mst1-JNK pathway; Sirt3; apoptosis; microglial BV-2 cells; neuroinflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Survival / drug effects
  • Down-Regulation
  • Gene Expression Regulation / drug effects
  • Inflammation / chemically induced
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Lipopolysaccharides / toxicity
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism
  • Mice
  • Microglia / drug effects*
  • Microglia / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Sirtuin 3 / genetics
  • Sirtuin 3 / metabolism*

Substances

  • Lipopolysaccharides
  • Sirt3 protein, mouse
  • Stk4 protein, mouse
  • Protein-Serine-Threonine Kinases
  • MAP Kinase Kinase 4
  • Sirtuin 3