Researchers have identified a mitochondrial enzyme, SIRT3, that helps neurons resist the kinds of energy and oxidative stress linked to aging and neurodegenerative diseases. In mouse studies, SIRT3 protected brain cells from insults that can deplete their energy and trigger degeneration, and voluntary exercise raised SIRT3 levels in neurons—linking physical activity to improved mitochondrial resilience.
A research team led by Mark P. Mattson, Ph.D., of the National Institute on Aging Intramural Research Program and Johns Hopkins University School of Medicine used novel animal and cellular models to study whether increasing neuronal stress resistance could counteract bioenergetic and excitotoxic challenges. Their work focuses on SIRT3, a mitochondrial protein deacetylase that regulates mitochondrial protein acetylation and influences cellular metabolism and antioxidant defenses.
Key findings from the study include:
- Mice genetically engineered to lack SIRT3 (Sirt3−/−) displayed markedly increased vulnerability to neurotoxins and to seizures that produce excitotoxic injury; neurons from these mice were more susceptible to degeneration under metabolic and oxidative stress.
- Normal mice given access to a running wheel showed higher SIRT3 expression in hippocampal neurons. This exercise-induced increase in SIRT3 corresponded with protection against neuronal damage, whereas mice lacking SIRT3 did not gain the same neuroprotective benefit from running.
- Restoring SIRT3 to neurons through adeno-associated virus (AAV)-mediated gene delivery enhanced neuronal resistance to energetic, oxidative, and excitatory stress, demonstrating that increasing SIRT3 levels can directly improve neuronal survival under challenge.
Together, these results indicate that boosting mitochondrial function and stress resistance by raising SIRT3 levels may offer a viable therapeutic approach to slow or prevent age-related cognitive decline and neurodegenerative disease progression. The authors report their findings online November 19, 2015, in the journal Cell Metabolism.
The study examined how mitochondrial protein acetylation, regulated by SIRT3, affects neuronal function and resistance to stress. In cultured cortical neurons, loss of SIRT3 led to increased susceptibility to glutamate-induced calcium overload, excitotoxicity, oxidative damage, and mitochondrial dysfunction. Conversely, delivering the Sirt3 gene via AAV restored resistance to these stresses, indicating a causative role for SIRT3 in neuronal protection.
In disease-relevant animal models, Sirt3−/− mice showed greater vulnerability of striatal neurons in a Huntington’s disease model and heightened sensitivity of hippocampal neurons in an epilepsy model. Mechanistically, SIRT3 deficiency caused hyperacetylation of several mitochondrial proteins, including the antioxidant enzyme superoxide dismutase 2 (SOD2) and the mitochondrial permeability regulator cyclophilin D—changes that likely undermine mitochondrial resilience.
The researchers also determined that the exercise-induced increase in hippocampal SIRT3 expression depends on excitatory glutamatergic neurotransmission. This pathway appears essential for maintaining mitochondrial protein acetylation balance and for enabling the neuroprotective benefits associated with voluntary running in mice.
Implications: The findings support the idea that SIRT3 is a central mediator of adaptive responses in neurons to physiological and pathological challenges. Strategies that enhance SIRT3 expression or activity—whether through lifestyle interventions such as aerobic exercise or through targeted gene- or drug-based therapies—could help preserve neuronal energy metabolism, reduce oxidative damage, and increase resistance to degeneration in aging and disease. While these results come from animal and cellular models and further research is required to translate findings to humans, the work highlights SIRT3 and mitochondrial acetylation as promising targets for interventions aimed at protecting brain health.
Abstract (paraphrased)
Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges
The study demonstrates that the mitochondrial deacetylase SIRT3 is crucial for neuronal adaptation to bioenergetic, oxidative, and excitatory stress. Neurons lacking SIRT3 show increased sensitivity to glutamate-driven calcium overload, excitotoxicity, and mitochondrial stress, whereas AAV-mediated Sirt3 delivery restores resistance. In models related to Huntington’s disease and epilepsy, Sirt3 knockout mice have greater neuronal vulnerability. Loss of SIRT3 causes hyperacetylation of mitochondrial proteins including SOD2 and cyclophilin D. Voluntary running elevates Sirt3 expression in hippocampal neurons through excitatory glutamatergic signaling, which is necessary for maintaining mitochondrial protein acetylation homeostasis and for the neuroprotective effects of exercise. The results indicate a pivotal role for SIRT3 in neuronal adaptive responses and resistance to degeneration.
Authors and credits: 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, National Institute on Aging Intramural Research Program.
Funding: 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
Original research: “Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges,” Cell Metabolism. Published online November 19, 2015. doi:10.1016/j.cmet.2015.10.013