Abstract
BackgroundSirtuins (Sirt), a family of nicotinamide adenine nucleotide (NAD) dependent deacetylases, are implicated in energy metabolism and life span. Among the known Sirt isoforms (Sirt1-7), Sirt3 was identified as a stress responsive deacetylase recently shown to play a role in protecting cells under stress conditions. Here, we demonstrated the presence of Sirt3 in neurons, and characterized the role of Sirt3 in neuron survival under NMDA-induced excitotoxicity.Methodology/Principal FindingsTo induce excitotoxic injury, we exposed primary cultured mouse cortical neurons to NMDA (30 µM). NMDA induced a rapid decrease of cytoplasmic NAD (but not mitochondrial NAD) in neurons through poly (ADP-ribose) polymerase-1 (PARP-1) activation. Mitochondrial Sirt3 was increased following PARP-1 mediated NAD depletion, which was reversed by either inhibition of PARP-1 or exogenous NAD. We found that massive reactive oxygen species (ROS) produced under this NAD depleted condition mediated the increase in mitochondrial Sirt3. By transfecting primary neurons with a Sirt3 overexpressing plasmid or Sirt3 siRNA, we showed that Sirt3 is required for neuroprotection against excitotoxicity.ConclusionsThis study demonstrated for the first time that mitochondrial Sirt3 acts as a prosurvival factor playing an essential role to protect neurons under excitotoxic injury.
Highlights
Continuous supply of energy is crucial for neuron survival due to the requirement for large amounts of energy for high metabolic processes coupled with an inability to store energy [1,2]
This study demonstrated for the first time that mitochondrial Sirt3 acts as a prosurvival factor playing an essential role to protect neurons under excitotoxic injury
nicotinamide adenine dinucleotide (NAD) was measured in both total cell fraction and mitochondria fraction of primary neuron cultures treated with 30 mM NMDA
Summary
Continuous supply of energy is crucial for neuron survival due to the requirement for large amounts of energy for high metabolic processes coupled with an inability to store energy [1,2]. Neurons are highly susceptible to insults that lead to energy depletion, such as oxidative stress, excitotoxicity, and DNA damage [3,4]. As a critical factor in energy metabolism for cell survival, nicotinamide adenine dinucleotide (NAD) has drawn considerable interest. NAD is an essential molecule playing a pivotal role in energy metabolism, cellular redox reaction, and mitochondrial function. Loss of NAD decreases the ability of NAD dependent cell survival factors to carry out energy dependent processes, leading to cell death. Sirtuins (Sirt), a family of nicotinamide adenine nucleotide (NAD) dependent deacetylases, are implicated in energy metabolism and life span. Among the known Sirt isoforms (Sirt1-7), Sirt was identified as a stress responsive deacetylase recently shown to play a role in protecting cells under stress conditions. We demonstrated the presence of Sirt in neurons, and characterized the role of Sirt in neuron survival under NMDA-induced excitotoxicity
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