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Sirtuin 3 regulates Foxo3a-mediated antioxidant pathway in microglia

P Rangarajan1, A Karthikeyan1, J Lu2

  • 1Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Neuroscience
|November 3, 2015
PubMed

Insights

Sirtuin 3 (Sirt3) acts as an antioxidant in microglia, reducing reactive oxygen species (ROS) by activating the transcription factor Foxo3a. This mechanism is crucial for protecting the brain against oxidative stress linked to neurodegenerative diseases.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Microglia are key sources of reactive oxygen species (ROS) in the central nervous system (CNS).
  • Chronic microglial activation and excessive ROS production contribute to oxidative stress implicated in neurodegenerative diseases like Alzheimer's and Parkinson's.
  • Sirtuin 3 (Sirt3) is a deacetylase known to regulate cellular ROS levels.

Purpose of the Study:

  • To investigate the expression and function of Sirtuin 3 (Sirt3) in microglia.
  • To elucidate the role of Sirt3 in regulating ROS production and oxidative stress in the brain.
  • To understand the molecular mechanism by which Sirt3 influences antioxidant gene expression.

Main Methods:

  • Localization of Sirt3 immunoreactivity in rat brain microglia.
  • Analysis of Sirt3 expression in lipopolysaccharide (LPS)-activated microglia and in response to traumatic brain injury (TBI).
  • In vitro studies involving Sirt3 knockdown and overexpression in microglia, assessing ROS levels, mitochondrial ROS, and antioxidant gene expression (Catalase, MnSOD).

Main Results:

  • Sirt3 expression was observed in ameboid microglia in early postnatal brains and diminished in adult brains, but was induced upon LPS activation and TBI.
  • Sirt3 knockdown increased cellular and mitochondrial ROS and decreased MnSOD expression in microglia.
  • Sirt3 overexpression elevated Catalase and MnSOD expression, alongside increased expression and nuclear translocation of Foxo3a.

Conclusions:

  • Sirt3 plays a critical role in the antioxidant defense of microglia by regulating ROS levels.
  • Sirt3 activates the transcription factor Foxo3a, leading to increased expression of antioxidant genes like Catalase and MnSOD.
  • The Sirt3-Foxo3a pathway represents a significant mechanism for mitigating oxidative stress in microglia, with implications for neuroprotection.
Keywords:
Foxo3aROSSirt3antioxidantbrain injurymicroglia

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