Effect of Sirt3 on hippocampal MnSOD activity, mitochondrial function, physiology, and cognition in an aged murine model

Behav Brain Res. 2023 Apr 27:444:114335. doi: 10.1016/j.bbr.2023.114335. Epub 2023 Feb 15.


The NAD(+)-dependent deacetylase SIRT3 is a proven mitochondrial metabolic stress sensor. It has been linked to the regulation of the mitochondrial acetylome and activation of several metabolic enzymes (e.g., manganese superoxide dismutase [MnSOD]) to protect mitochondrial function and redox homeostasis, which are vital for survival, excitability, and synaptic signaling of neurons mediating short- and long-term memory formation as well as retention. Eighteen-month-old male and female wild-type (WT) and Sirt3-/- mice were behaviorally tested for hippocampus-dependent cognitive performance in a Morris water maze paradigm. Cognitive impairment was displayed during the probe trial by female and male Sirt3-/- mice but not WT mice. Upon sacrifice, brains were fixed, and morphological assessments were conducted on hippocampal tissues. Both female and male Sirt3-/- mice demonstrated impaired spatial memory retention implying that SIRT3 plays a role in long-term memory function. Golgi-staining studies revealed decreased dendritic arborization and dendritic length in the hippocampi of male Sirt3-/- compared to WT animals. Sirt3 deletion significantly increased NR1, NR2A, and NR2B expression in the hippocampus of female mice only. Enzymatic activity of MnSOD, a major mitochondrial deacetylation target of SIRT3, was significantly decreased in both female and male Sirt3-/- mice. Similarly, both female and male Sirt3-/- mice demonstrated a significant decrease in their respiratory control ratio during Complex I-driven respiration, which was apparent only in female Sirt3-/- mice during Complex II-driven respiration.

Keywords: Dendritic morphology; Hippocampus; Mitochondrial dysfunction; MnSOD; Sirt3(-/-).

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Wild / metabolism
  • Antioxidants / metabolism
  • Cognition
  • Disease Models, Animal
  • Female
  • Hippocampus / metabolism
  • Male
  • Mice
  • Mitochondria / metabolism
  • Oxidative Stress / physiology
  • Sirtuin 3* / metabolism
  • Superoxide Dismutase / metabolism


  • Sirtuin 3
  • Antioxidants
  • Superoxide Dismutase
  • Sirt3 protein, mouse