Abstract
Progressive mitochondrial dysfunction contributes to neuronal degeneration in age-mediated disease. An essential regulator of mitochondrial function is the deacetylase, sirtuin 3 (SIRT3). Here we investigate a role for CNS Sirt3 in mitochondrial responses to reactive oxygen species (ROS)- and Alzheimer’s disease (AD)-mediated stress. Pharmacological augmentation of mitochondrial ROS increases Sirt3 expression in primary hippocampal culture with SIRT3 over-expression being neuroprotective. Furthermore, Sirt3 expression mirrors spatiotemporal deposition of β-amyloid in an AD mouse model and is also upregulated in AD patient temporal neocortex. Thus, our data suggest a role for SIRT3 in mechanisms sensing and tackling ROS- and AD-mediated mitochondrial stress.
Highlights
Decline in cognition is closely associated with age-related structural and functional changes of neurons leading to synaptic dysfunction [1]
Since mitochondrial oxidative stress is a hallmark of several neuropathological diseases, including Alzheimer’s disease (AD), we aimed to investigate whether interference with the electron transport chain (ETC) and induction of reactive oxygen species (ROS) could trigger changes in Sirt3 expression
Our in vitro, AD mouse model and human AD post mortem tissue data suggest a neuroprotective role for sirtuin 3 (SIRT3) in CNS mechanisms dealing with mitochondrial stress, including during AD progression
Summary
Decline in cognition is closely associated with age-related structural and functional changes of neurons leading to synaptic dysfunction [1]. A mitochondrial protein that has been shown to be critical for the maintenance of appropriate ROS levels and ATP output is the sirtuin family member, SIRT3 [4,5]. SIRT3 is upregulated in response to fasting and calorie restriction and has been shown to reduce ROS levels in adipocytes [7] and cardiomyocytes [8] and to reduce oxidative damage and enhance the mitochondrial glutathione antioxidant defense system in cochlear neurons [9]. Substrates activated by SIRT3-mediated deacetylation include a number of proteins critical for the maintenance of mitochondrial metabolic balance[4,5,9,10,11,12,13,14,15], and SIRT3-deficient mice show significantly enhanced acetylation of these, leading to increased oxidative damage in multiple tissues [9,16]. Kim et al demonstrated that SIRT3 is neuroprotective against NMDA-mediated excitotoxicity in vitro [17]
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