Oxidized nicotinamide adenine dinucleotide-dependent mitochondrial deacetylase sirtuin-3 as a potential therapeutic target of Parkinson's disease

Mitochondrial impairment is associated with progressive dopamine (DA) neuron degeneration in Parkinson's disease (PD). Recent findings highlight that Sirtuin-3 (SIRT3), a mitochondrial protein, is an oxidized nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase and a key modulator in maintaining integrity and functions of mitochondria. SIRT3 plays vital roles in regulation of mitochondrial functions, including mitochondrial ATP generation and energy metabolism, anti-oxidant defense, and cell death and proliferation. SIRT3 can deacetylate the transcriptional factors and crosstalk with different signaling pathways to cooperatively modulate mitochondrial functions and regulate defensive mitochondrial quality control (QC) systems. Down-regulated NAD+ level and decreased SIRT3 activity are related to aging process and has been pathologically linked to PD pathogenesis. Further, SIRT3 can bind and deacetylate PTEN-induced kinase 1 (PINK1) and PD protein 2 E3 ubiquitin protein ligase (Parkin) to facilitate mitophagy. Leucine Rich Repeat Kinase 2 (LRRK2)-G2019S mutation in PD is linked to SIRT3 impairment. Furthermore, SIRT3 is inversely associated with alpha-synuclein aggregation and DA neuron degeneration in PD. SIRT3 chemical activators and NAD + precursors can up-regulate SIRT3 activity to protect against DA neuron degeneration in PD models. Taken together, SIRT3 is a promising PD therapeutic target and studies of SIRT3 functional modulators with neuroprotective capability will be of clinical interest.