Sirt3 protects dopaminergic neurons from mitochondrial oxidative stress

Abstract

Age-dependent elevation in mitochondrial oxidative stress is widely posited to be a major factor underlying the loss of substantia nigra pars compacta (SNc) dopaminergic neurons in Parkinson's disease (PD). However, mechanistic links between aging and oxidative stress are not well understood. Sirtuin-3 (Sirt3) is a mitochondrial deacetylase that could mediate this connection. Indeed, genetic deletion of Sirt3 increased oxidative stress and decreased the membrane potential of mitochondria in SNc dopaminergic neurons. This change was attributable to increased acetylation and decreased activity of manganese superoxide dismutase (MnSOD). Site directed mutagenesis of lysine 68 to glutamine (K68Q), mimicking acetylation, decreased MnSOD activity in SNc dopaminergic neurons, whereas mutagenesis of lysine 68 to arginine (K68R), mimicking deacetylation, increased activity. Introduction of K68R MnSOD rescued mitochondrial redox status and membrane potential of SNc dopaminergic neurons from Sirt3 knockouts. Moreover, deletion of DJ-1, which helps orchestrate nuclear oxidant defenses and Sirt3 in mice led to a clear age-related loss of SNc dopaminergic neurons. Lastly, K68 acetylation of MnSOD was significantly increased in the SNc of PD patients. Taken together, our studies suggest that an age-related decline in Sirt3 protective function is a major factor underlying increasing mitochondrial oxidative stress and loss of SNc dopaminergic neurons in PD.

SIRT3 activator honokiol ameliorates surgery/anesthesia‐induced cognitive decline in mice through anti‐oxidative stress and anti‐inflammatory in hippocampus

“…SIRT3 is the one member of the sirtuin family that exhibits deacetylase activity and is mainly localized to the mitochondria. Regarding to oxidative stress, SIRT3 mainly regulates mitochondrial ROS levels by deacetylating SOD2 and has a positive role in several neurological disorders, including AD, PD and Huntington's disease . And with the downregulated of oxidative stress, the inflammatory and related cytokines can also be normalized.…”

“…Regarding to oxidative stress, SIRT3 mainly regulates mitochondrial ROS levels by deacetylating SOD2 and has a positive role in several neurological disorders, including AD, PD and Huntington's disease. [53][54][55][56] And with the downregulated of oxidative stress, the inflammatory and related cytokines can also be normalized. Second, in current studies, our just tested the surgery/anesthesiainduced neuroinflammatory and oxidative stress in hippocampus of mice, but other region in brain (such as prefrontal cortex) and systemic inflammation was not investigated.…”

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…In addition, recent findings suggest that intermittent metabolic switching enhances the function, stress resistance, and quality control of mitochondria, in part by inducing the expression of the mitochondrial protein deacetylase SIRT3. The activities of ETC proteins and the mitochondrial antioxidant enzyme SOD2 are enhanced when deacetylated by SIRT3, while deacetylation of cyclophilin D can inhibit formation of mPTPs, thereby preventing neuronal excitotoxicity and apoptosis (Cheng et al, 2016; Shi et al, 2017). …”

Imbalance of Lysine Acetylation Contributes to the Pathogenesis of Parkinson’s Disease

“…MPP + treatment also decreases SIRT3 expression and leads to increased acetylation of citrate synthase (CS) and isocitrate dehydrogenase 2 (IDH2) and decreased enzymatic activity of these proteins ( Figure 5 ) [ 70 ]. SIRT3 deacetylates SOD2 at the K68 site and increases its ROS-eliminating activity, thus repressing DA neuronal degeneration in PD [ 68 ]. Lysine acetylation changes are detectable in the mitochondria in A53T-α-syn/ PINK -/- mice compared with wild-type controls, and SIRT3 levels are significantly decreased [ 125 ].…”