Sirtuins at the Crossroads between Mitochondrial Quality Control and Neurodegenerative Diseases: Structure, Regulation, Modifications, and Modulators

Abstract

Sirtuins (SIRT1-SIRT7), a family of nicotinamide adenine dinucleotide (NAD⁺)-dependent enzymes, are key regulators of life span and metabolism. In addition to acting as deacetylates, some sirtuins have the properties of deacylase, decrotonylase, adenosine diphosphate (ADP)-ribosyltransferase, lipoamidase, desuccinylase, demalonylase, deglutarylase, and demyristolyase. Mitochondrial dysfunction occurs early on and acts causally in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Sirtuins are implicated in the regulation of mitochondrial quality control, which is highly associated with the pathogenesis of neurodegenerative diseases. There is growing evidence indicating that sirtuins are promising and well-documented molecular targets for the treatment of mitochondrial dysfunction and neurodegenerative disorders by regulating mitochondrial quality control, including mitochondrial biogenesis, mitophagy, mitochondrial fission/fusion dynamics, and mitochondrial unfolded protein responses (mtUPR). Therefore, elucidation of the molecular etiology of sirtuin-mediated mitochondrial quality control points to new prospects for the treatment of neurodegenerative diseases. However, the mechanisms underlying sirtuin-mediated mitochondrial quality control remain obscure. In this review, we update and summarize the current understanding of the structure, function, and regulation of sirtuins with an emphasis on the cumulative and putative effects of sirtuins on mitochondrial biology and neurodegenerative diseases, particularly their roles in mitochondrial quality control. In addition, we outline the potential therapeutic applications for neurodegenerative diseases of targeting sirtuin-mediated mitochondrial quality control through exercise training, calorie restriction, and sirtuin modulators in neurodegenerative diseases.

Figure 1.

Multiple enzymatic functions of sirtuins. Sirtuins are a family of NAD⁺-dependent enzymes. SIRT1, SIRT2, SIRT4, and SIRT6 display deacylase activity. SIRT3 exhibits decrotonylase activity. SIRT4 and SIRT6 exhibit ADP-ribosyl transferase activity. SIRT5 is a cofactor in the desuccinylation and demalonylation of target proteins. SIRT7 show desuccinylase activity.

Figure 2.

Structure and subcellular localization of human sirtuins. The positions of the amino acid are indicated on each schematic. Domains are shown in different colors.

Figure 3.

Mechanisms of action that regulate sirtuin expression. The regulatory mechanisms of sirtuin expression include transcriptional regulation and post-transcriptional regulation.

Figure 4.

Post-translational modifications of sirtuins. Sirtuins can be affected by post-translational modifications, including phosphorylation, ubiquitination, SUMOylation, methylation, acetylation, O-GlcNAcylation, S-nitrosylation, and S-glutathionylation.

Figure 5.

Mitochondrial quality control. (A) Mitochondrial biogenesis. Once activated by either deacetylation or phosphorylation, proliferator-activated receptor γ coactivator 1α (PGC-1α) triggers the activation of the nuclear respiratory factors (NRFs)/mitochondrial transcription factor A (TFAM) pathway, promoting mitochondrial biogenesis. (B) Mitophagy. The phosphatase and tensin homolog-induced putative protein kinase 1 (PINK1)/Parkin-mediated mitophagy pathway is involved in the formation of autophagosomes. (C) Mitochondrial dynamics. Mitochondrial fission is regulated by dynamin-related protein 1 (DRP1) and fission protein 1 (FIS1), whereas mitochondrial fusion is modulated by mitofusin (MFN) 1/2 and optic atrophy 1 (OPA1). (D) Mitochondrial unfolded protein response. Molecular chaperones and proteases mediate the degradation or refolding of misfolded/unfolded mitochondrial proteins.

Figure 6.

Sirtuin-mediated mitochondrial quality control in neurodegeneration. SIRT1 catalyzes the deacetylation of proliferator-activated receptor γ coactivator 1α (PGC-1α), AMP-activated protein kinase (AMPK), forkhead box class O3 (FOXO3), mitofusin (MFN), signal transducer and activator of transcription 3 (STAT3), and endothelial nitric oxide synthase (eNOS) and participates in mitochondrial quality control. PINK1/Parkin pathway-mediated mitophagy is activated by either the SIRT1/FOXO3 axis or SIRT3. Additionally, SIRT2 is involved in mitochondrial fission by regulating DRP1 via the SIRT2/mitogen-activated protein kinase kinase-1 (MEK1)/extracellular signal-regulated kinase (ERK)/dynamin-related protein 1 (DRP1) and SIRT2/serine/threonine-protein kinase AKT1/DRP1 pathways. Autophagy protein (ATG) 5/32-mediated mitophagy is regulated by SIRT2. SIRT3 deacetylates HSP10 and Lon proteases and regulates mitochondrial unfolded protein response (mtUPR). Liver kinase B (LKB), mitochondrial transcription factor A (TFAM), FOXO3, and optic atrophy type 1 (OPA1) have been identified as SIRT3 substrates. Additionally, SIRT4 modulates mitochondrial dynamics by regulating OPA1.