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 journalArticle

Abstract

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
Volume23
Issue number1
DOIs
StatePublished - Jan 12 2016

Fingerprint

Mitochondrial Proteins
Neurons
Acetylation
Running
Oxidative Stress
Corpus Striatum
Huntington Disease
Neuroprotective Agents
Nervous System Diseases
Synaptic Transmission
Energy Metabolism
Glutamic Acid
Epilepsy
Homeostasis
Calcium
Genes

Keywords

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

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges. / Cheng, Aiwu; Yang, Ying; Zhou, Ye; Maharana, Chinmoyee; Lu, Daoyuan; Peng, Wei; Liu, Yong; Wan, Ruiqian; Marosi, Krisztina; Misiak, Magdalena; Bohr, Vilhelm A.; Mattson, Mark P.

In: Cell Metabolism, Vol. 23, No. 1, 12.01.2016, p. 128-142.

Research output: Contribution to journalArticle

Cheng, A, Yang, Y, Zhou, Y, Maharana, C, Lu, D, Peng, W, Liu, Y, Wan, R, Marosi, K, Misiak, M, Bohr, VA & Mattson, MP 2016, 'Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges', Cell Metabolism, vol. 23, no. 1, pp. 128-142. https://doi.org/10.1016/j.cmet.2015.10.013
Cheng, Aiwu ; Yang, Ying ; Zhou, Ye ; Maharana, Chinmoyee ; Lu, Daoyuan ; Peng, Wei ; Liu, Yong ; Wan, Ruiqian ; Marosi, Krisztina ; Misiak, Magdalena ; Bohr, Vilhelm A. ; Mattson, Mark P. / Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges. In: Cell Metabolism. 2016 ; Vol. 23, No. 1. pp. 128-142.
@article{71ce3e11ea204471b3ae0c6a8d7b9f85,
title = "Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges",
abstract = "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.",
keywords = "CypD, excitotoxicity, mitochondria, mPTP, neurodegeneration, ROS, SOD2, voluntary exercise",
author = "Aiwu Cheng and Ying Yang and Ye Zhou and Chinmoyee Maharana and Daoyuan Lu and Wei Peng and Yong Liu and Ruiqian Wan and Krisztina Marosi and Magdalena Misiak and Bohr, {Vilhelm A.} and Mattson, {Mark P.}",
year = "2016",
month = "1",
day = "12",
doi = "10.1016/j.cmet.2015.10.013",
language = "English (US)",
volume = "23",
pages = "128--142",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "1",

}

TY - JOUR

T1 - Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges

AU - Cheng, Aiwu

AU - Yang, Ying

AU - Zhou, Ye

AU - Maharana, Chinmoyee

AU - Lu, Daoyuan

AU - Peng, Wei

AU - Liu, Yong

AU - Wan, Ruiqian

AU - Marosi, Krisztina

AU - Misiak, Magdalena

AU - Bohr, Vilhelm A.

AU - Mattson, Mark P.

PY - 2016/1/12

Y1 - 2016/1/12

N2 - 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.

AB - 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.

KW - CypD

KW - excitotoxicity

KW - mitochondria

KW - mPTP

KW - neurodegeneration

KW - ROS

KW - SOD2

KW - voluntary exercise

UR - http://www.scopus.com/inward/record.url?scp=84955371298&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84955371298&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2015.10.013

DO - 10.1016/j.cmet.2015.10.013

M3 - Article

VL - 23

SP - 128

EP - 142

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 1

ER -