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.

Intermittent metabolic switching, neuroplasticity and brain health

“…To illustrate this point, we highlight the mitochondrial NAD + -dependent protein deacetylase SIRT3, which is emerging as a key mediator of adaptive responses of neurons to bioenergetic challenges 68 . SIRT3 expression is upregulated in the cerebral cortical and hippocampal neurons of mice in response to running-wheel exercise by a mechanism requiring activation of NMDA glutamate receptors 69 . Deletion of SIRT3 from neurons renders them vulnerable to excitotoxicity and mitochondrial stress, whereas overexpression of SIRT3 is neuroprotective 69 .…”

“…SIRT3 expression is upregulated in the cerebral cortical and hippocampal neurons of mice in response to running-wheel exercise by a mechanism requiring activation of NMDA glutamate receptors 69 . Deletion of SIRT3 from neurons renders them vulnerable to excitotoxicity and mitochondrial stress, whereas overexpression of SIRT3 is neuroprotective 69 . SIRT3-mediated deacetylation of proteins in the electron transport chain and tricarboxylic acid (TCA) cycle may enhance the efficiency of mitochondrial ATP production, whereas deacetylation of superoxide dismutase 2 reduces mitochondrial oxidative stress and deacetylation of cyclophilin D protects neurons against apoptosis 69,70 (FIG.…”

Mitochondrial Sirtuins and Molecular Mechanisms of Aging

“…In line with these observations, cultured neurons from Sirt3-deficient mice have been reported to display increased sensitivity to cell death in response to oxidative and metabolic stress, as well as excitotoxicoly -- a phenomenon where neurons are damaged and killed in response to overstimulation [88]. In terms of neurodegenerative brain diseases, Sirt3-deficient mice have been shown to display increased neuronal damage in models approximating Huntington’s Disease and epilepsy [88]. Neuronal damage in these mice appears to occur through hyperacetylation of SOD2 and cyclophilin D, a component of the mitochondrial permeability transition pore [88].…”

“…Interestingly, stimulation of NAD + levels by dietary supplementation with the NAD + precursor nicotinamide riboside was shown to be sufficient to rescue animals from NIHL, whereas Sirt3-deficient animals did not respond to this treatment. In line with these observations, cultured neurons from Sirt3-deficient mice have been reported to display increased sensitivity to cell death in response to oxidative and metabolic stress, as well as excitotoxicoly -- a phenomenon where neurons are damaged and killed in response to overstimulation [88]. In terms of neurodegenerative brain diseases, Sirt3-deficient mice have been shown to display increased neuronal damage in models approximating Huntington’s Disease and epilepsy [88].…”

“…In terms of neurodegenerative brain diseases, Sirt3-deficient mice have been shown to display increased neuronal damage in models approximating Huntington’s Disease and epilepsy [88]. Neuronal damage in these mice appears to occur through hyperacetylation of SOD2 and cyclophilin D, a component of the mitochondrial permeability transition pore [88]. Of note, neuronal Sirt3 levels were increased after mild in vitro excitation with the neurotransmitter glutamate and following voluntarily exercise, which suggests that modulating SIRT3 levels via glutamate could have therapeutic potential in neurodegenerative disorders.…”