Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges

Aiwu Cheng, Ying Yang, Ye Zhou, Chinmoyee Maharana, Daoyuan Lu, Wei Peng, Yong Liu, Ruiqian Wan, Krisztina Marosi, Magdalena Misiak, Vilhelm A. Bohr, Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

152 Scopus citations


The impact of mitochondrial protein acetylation status on neuronal function and vulnerability to neurological disorders is unknown. Here we show that the mitochondrial protein deacetylase SIRT3 mediates adaptive responses of neurons to bioenergetic, oxidative, and excitatory stress. Cortical neurons lacking SIRT3 exhibit heightened sensitivity to glutamate-induced calcium overload and excitotoxicity and oxidative and mitochondrial stress; AAV-mediated Sirt3 gene delivery restores neuronal stress resistance. In models relevant to Huntington's disease and epilepsy, Sirt3-/- mice exhibit increased vulnerability of striatal and hippocampal neurons, respectively. SIRT3 deficiency results in hyperacetylation of several mitochondrial proteins, including superoxide dismutase 2 and cyclophilin D. Running wheel exercise increases the expression of Sirt3 in hippocampal neurons, which is mediated by excitatory glutamatergic neurotransmission and is essential for mitochondrial protein acetylation homeostasis and the neuroprotective effects of running. Our findings suggest that SIRT3 plays pivotal roles in adaptive responses of neurons to physiological challenges and resistance to degeneration.

Original languageEnglish (US)
Pages (from-to)128-142
Number of pages15
JournalCell Metabolism
Issue number1
StatePublished - Jan 12 2016


  • CypD
  • excitotoxicity
  • mitochondria
  • mPTP
  • neurodegeneration
  • ROS
  • SOD2
  • voluntary exercise

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology


Dive into the research topics of 'Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges'. Together they form a unique fingerprint.

Cite this