As we age or develop neurodegenerative diseases such as Alzheimer’s, our brain cells may not produce sufficient energy to remain fully functional. Researchers discovered that an enzyme called SIRT3 that is located in mitochondria — the cell’s powerhouse — may protect mice brains against the kinds of stresses believed to contribute to energy loss. Furthermore, mice that ran on a wheel increased their levels of this protective enzyme.
Researchers led by Mark Mattson, Ph.D., of the National Institute on Aging Intramural Research Program and Johns Hopkins University School of Medicine, used a new animal model to investigate whether they could aid neurons in resisting the energy-depleting stress caused by neurotoxins and other factors.
They found the following:
- Mice models that did not produce SIRT3 became highly sensitive to stress when exposed to neurotoxins that cause neurodegeneration and epileptic seizures.
- Running wheel exercise increased the amount of SIRT3 in neurons of normal mice and protected them against degeneration; in those lacking the enzyme, running failed to protect the neurons.
- Neurons could be protected against stress through use of a gene therapy technology to increase levels of SIRT3 in neurons.
These findings suggest that bolstering mitochondrial function and stress resistance by increasing SIRT3 levels may offer a promising therapeutic target for protecting against age-related cognitive decline and brain diseases. The research team report their findings online Nov. 19 in the journal Cell Metabolism.
Other authors on the paper are Aiwu Cheng, Ying Yang, Ye Zhou, Chinmoyee Maharana, Daoyuan Lu, Wei Peng, Yong Liu, Ruiqian Wan, Krisztina Marosi, Magdalena Misiak and Vilhelm A. Bohr, all of the National Institute on Aging Intramural Research Program.
Funding: This work was supported by the Intramural Research Program of the National Institute on Aging and the Glenn Foundation for Biomedical Research.
Source: Shawna Williams – Johns Hopkins Medicine
Image Source: The image is in the public domain
Original Research: Abstract for “Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges” by Aiwu Cheng, Ying Yang, Ye Zhou, Chinmoyee Maharana, Daoyuan Lu, Wei Peng, Yong Liu, Ruiqian Wan, Krisztina Marosi, Magdalena Misiak, Vilhelm A. Bohr, and Mark P. Mattson in Cell Metabolism. Published online November 19 2015 doi:10.1016/j.cmet.2015.10.013
Abstract
Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges
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.
“Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges” by Aiwu Cheng, Ying Yang, Ye Zhou, Chinmoyee Maharana, Daoyuan Lu, Wei Peng, Yong Liu, Ruiqian Wan, Krisztina Marosi, Magdalena Misiak, Vilhelm A. Bohr, and Mark P. Mattson in Cell Metabolism. Published online November 19 2015 doi:10.1016/j.cmet.2015.10.013
