ReviewMitochondrial sirtuins: Emerging roles in metabolic regulations, energy homeostasis and diseases
Introduction
Sirtuins are conserved family of proteins that depend on nicotinamide adenine dinucleotide (NAD+) for their deacetylase activity (North and Verdin, 2004, Sauve and Youn, 2012). They are involved in various biological functions (Finkel et al., 2009) such as control of aging (Tissenbaum and Guarente, 2001, Wood et al., 2004), longevity pathways (Gan and Mucke, 2008), DNA repair (Lombard et al., 2008), transcriptional silencing (Tissenbaum and Guarente, 2001), apoptosis (Cohen et al., 2004, Wang et al., 2006) and the control of metabolic enzymes (Schwer and Verdin, 2008). Apart from all these functions sirtuins mainly function as anti-aging genes and their NAD+ dependence categorize them as a link between aging and metabolism (Guarente, 2007). Sirtuins are considered as histone deacetylases (HDACs) class III enzymes because of their dependence on NAD+ as cofactor for protein deacetylation (North and Verdin, 2004). However, sirtuins are functionally different from other classes of HDACs, as they carry out deacetylation via a two step reaction that consumes NAD+ and releases nicotinamide (NAM), 1-O-acetyl-ADP-ribose (1-O-AADPR), and the deacetylated substrate (Haigis and Guarente, 2006) (Fig. 1).
There are seven mammalian sirtuins ranging from Sirt1 to Sirt7 that have distinct flanking N- and C-terminal extensions. These variations in their N and C termini are responsible for the subcellular localization of sirtuins as described in Table 1 (Haigis and Sinclair, 2010). All types of sirtuins are variable in length and sequence (Brachmann et al., 1995, Frye, 1999) but have a highly conserved catalytic core domain of approximately 275 amino acids (Frye, 2000). This catalytic core region contains a large and structurally homologous NAD+/NADH binding Rossmann-fold domain, zinc-binding domain and several loops that form a pronounced and extended cleft. This cleft connects the two domains where the NAD+ and acetyl lysine containing peptide substrates enter and bind to the enzyme for deacetylation (Sanders et al., 2010).
On the basis of phylogenetic conservation of this core domain the sirtuins are classified into five subclasses (I–IV and U) (Frye, 1999, Frye, 2000). Classes I–IV are the mammalian sirtuins. Class I sirtuins are Sirt1, 2, and 3 that exhibit deacetylase activity. Class II sirtuin includes Sirt4, that shows weak ADP-ribosyltransferase activity (Haigis et al., 2006, Ahuja et al., 2007). However, this ADP-ribosyltransferase activity of sirtuins may be due to some inefficient side reactions of the deacetylase activity and may not be physiologically relevant (Du et al., 2009). Class III sirtuin includes Sirt5 that shows deacylase activity (Yu et al., 2013) and weak deacetylase activity on histone substrates (Nakagawa et al., 2009). Class IV sirtuins include Sirt6 and Sirt7 which have ADP ribosyltransferase and deacetylase activities (Kawahara et al., 2009). In a recent study Jiang et al. (2013) found that Sirt6, which has weak deacetylase activities in vitro, catalyzes the hydrolysis of fatty acyl lysine modifications thus functions as long chain deacylase. These mammalian sirtuins occupy different subcellular compartments, such as the nucleus (Sirt1, Sirt2, Sirt3, Sirt6, Sirt7), cytoplasm (Sirt1, Sirt2), and mitochondria (Sirt3, Sirt4, Sirt5) (Michishita et al., 2005). Class U sirtuins, observed in archae and bacteria are intermediate between classes I and IV (Frye, 2000). Although an enormous progress has been made in recent years in the field of mitochondrial sirtuins however, at present the mechanisms involving the role of mitochondrial sirtuins in a variety of metabolic reactions and human diseases are not well understood. Thus in this review we highlight the recent views on the role of mitochondrial sirtuins in the metabolic regulations, apoptosis, mitochondrial biogenesis and how these mitochondrial sirtuins affect the progression of diseases (Fig. 2).
Section snippets
Mitochondrial Sirtuins: localization, enzymatic activity and regulation
Mitochondrial sirtuins are metabolic sensors of cell's energetic status because of its dependence on NAD+ as a cofactor (Zhong and Mostoslavsky, 2011). The three mitochondrial sirtuins: Sirt3, Sirt4, and Sirt5 are localized mainly in the mitochondrial matrix because of having mitochondrion targeting sequences in their N termini (Lombard et al., 2007) (Table 1). Among these three mitochondrial sirtuins, Sirt3 is the major mitochondrial deacetylase (Lombard et al., 2007) responsible for the
Mitochondrial sirtuins in metabolism and energy production
The mitochondria provide the hub for the metabolism of carbohydrate, lipids, and proteins. During metabolic conversions the mitochondrial proteins are subjected to posttranslational modifications. Lysine acetylation is a conserved posttranslational modification that links acetyl CoA metabolism and cellular signaling (Choudhary et al., 2014). Proteomic studies such as mass spectrometry data revealed that a large fraction of mitochondrial proteins such as enzymes of tricarboxylic acid (TCA)
Mitochondrial sirtuins in modulation of ROS and oxidative stress
Mitochondria are key regulators of cell survival and death. Mitochondrial energy metabolism impairment accounts for majority of cellular oxidative stress, with ROS formation (Beal, 2005). Thus mitochondria have developed numerous biological programs to cope with oxidative stress and maintain functional homeostasis. Among all mitochondrial sirtuins, Sirt3 is a major deacetylase responsible for maintaining cellular ROS levels via enhancing the antioxidant defence system (Bell and Guarente, 2011).
Mitochondrial sirtuins in apoptosis
Apoptosis is a cellular process of programmed cell death. Mitochondria play an important role in apoptosis by a variety of key events including the release of caspase activators (such as cytochrome c), changes in electron transport, loss of mitochondrial transmembrane potential, altered cellular oxidation–reduction, participation of pro-apoptotic and anti-apoptotic Bcl-2 family protein and the activation of mitochondrial outer membrane permeabilization. In addition to their roles in ROS
Mitochondrial sirtuins in mitochondrial biogenesis
Mitochondria play central roles in energy homeostasis, metabolism, signaling, and apoptosis that depend on the abundance, morphological properties, and functional properties of mitochondria. The interdependence between the properties and the functions of mitochondria can be stabilized at the level of transcriptional regulation. A broad set of nuclear genes encodes mitochondrial proteins that control replication and transcription of the mitochondrial genome which are regulated by various types
In metabolic impairments
The metabolic impairment is characterized by hypertension, obesity, insulin resistance and hyperlipidemia (Reaven, 1988). The prevalence of metabolic impairments varies and depends on many factors including sex, age, race and ethnicity of the population. The major cause of metabolic impairment has been related to the physical inactivity, high calorie diet, increased inflammation, reduced fatty acid oxidation, increased oxidative stress, and aging (Petersen et al., 2004, Uysal et al., 1997, Ji
In prevention of diseases: sirtuins as a target for bioactive compounds
Mitochondrial sirtuins have been found to regulate many aspects of mitochondrial function, such as metabolism, ATP generation and modulation of energy homeostasis. The role of mitochondrial sirtuins in the regulation of energy homeostasis may have far-reaching consequences for many diseases. The prominent role of mitochondrial sirtuins in metabolic regulations proves them fascinating targets for drugs (Milne and Denu, 2008). However, despite the recent discoveries on the role of mitochondrial
Conclusion and future perspectives
Sirtuins are highly conserved NAD+-dependent protein deacetylases or ADP ribosyl transferases involved in many cellular processes including genome stability, cell survival, oxidative stress responses, metabolism, and aging. Mitochondrial sirtuins, Sirt3, Sirt4 and Sirt5 are important energy sensors and thus can be regarded as master regulators of mitochondrial metabolism. But it is still not known whether specific sirtuin can only function within particular metabolic pathways or two or more
Acknowledgments
Authors gratefully acknowledge the financial support from the Department of Science and Technology, New Delhi (INSPIRE-DST to Priyanka Parihar, IF120382).
References (153)
- et al.
Regulation of insulin secretion by SIRT4, a mitochondrial ADP ribosyltransferase
J. Biol. Chem.
(2007) - et al.
SIRT3 is regulated by nutrient excess and modulates hepatic susceptibility to lipotoxicity
Free Radic. Biol. Med.
(2010) - et al.
The SirT3 divining rod points to oxidative stress
Mol. Cell
(2011) - et al.
A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages
Genomics
(2005) Ammonia toxicity to the brain: effects on creatine metabolism and transport and protective roles of creatine
Mol. Genet. Metab.
(2010)- et al.
Mitochondrial transcription factor A regulates mitochondrial transcription initiation, DNA packaging, and genome copy number
Biochim. Biophys. Acta
(2012) - et al.
Acetylation of the C terminus of Ku70 by CBP and PCAF controls bax-mediated apoptosis
Mol. Cell
(2004) The neurobiology of sirtuins and their role in neurodegeneration
Trends Pharmacol. Sci.
(2012)- et al.
SIRT3 opposes reprogramming of cancer cell metabolism through HIF1alpha destabilization
Cancer Cell
(2011) Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity
Biochem. Biophys. Res. Commun.
(1999)
Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins
Biochem. Biophys. Res. Commun.
Trans-(−)-ε-viniferin increases mitochondrial sirtuin 3 (SIRT3), activates AMP-activated protein kinase (AMPK), and protects cells in models of Huntington disease
J. Biol. Chem.
Paths of convergence: sirtuins in aging and neurodegeneration
Neuron
Peroxisome proliferator-activated receptor-{gamma} coactivator-1{alpha} controls transcription of the Sirt3 gene, an essential component of the thermogenic brown adipocyte phenotype
J. Biol. Chem.
Hypoxia-inducible factors: central regulators of the tumor phenotype
Curr. Opin. Genet. Dev.
SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells
Cell
Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction
Mol. Cell
SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome
Mol. Cell
Crystal structure of the bovine mitochondrial elongation factor Tu.Ts complex
J. Biol. Chem.
Reduced capacity for fatty acid oxidation in rats with inherited susceptibility to diet-induced obesity
Metab. Clin. Exp.
AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism
Cell Metab.
SIRT6 links histone H3 lysine 9 deacetylation to NF-κB-dependent gene expression and organismal life span
Cell
Substrate and functional diversity of lysine acetylation revealed by a proteomics survey
Mol. Cell
SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress
Cancer Cell
SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase
Mol. Cell
Sirtuins regulate key aspects of lipid metabolism
Biochim. Biophys. Acta
The sirtuin family: therapeutic targets to treat diseases of aging
Curr. Opin. Chem. Biol.
Complex III releases superoxide to both sides of the inner mitochondrial membrane
J. Biol. Chem.
SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle
Cell
SIRT5 deacetylates and activates urate oxidase in liver mitochondria of mice
FEBS Lett.
Immunoaffinity purification of mammalian protein complexes
Methods Enzymol.
SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells
J. Biol. Chem.
Mitochondrial protein acylation and intermediary metabolism: regulation by sirtuins and implications for metabolic disease
J. Biol. Chem.
The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase
Molecular cell
Sirtuins: a conserved key unlocking AceCS activity
Trends Biochem. Sci.
Mutual dependence of Foxo3a and PGC-1α in the induction of oxidative stress genes
J. Biol. Chem.
SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways
Mol. Cell
Mitochondrial bound type II hexokinase: a key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention
Biochim. Biophys. Acta
A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis
Proc. Natl. Acad. Sci. U. S. A.
SIRT3 is pro-apoptotic and participates in distinct basal apoptotic pathways
Cell Cycle
Altered sirtuin expression is associated with node-positive breast cancer
Br. J. Cancer
Less stress, longer life
Nat. Med.
SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production
Oncogene
The SIR2 gene family, conserved from bacteria to humans, functions in silencing, cell cycle progression, and chromosome stability
Genes Dev.
Glutamine metabolism is essential for human cytomegalovirus infection
J. Virol.
Tumour suppressor SIRT3 deacetylates and activates manganese superoxide dismutase to scavenge ROS
EMBO Rep.
Sirtuin-3 (SIRT3), a therapeutic target with oncogenic and tumor-suppressive function in cancer
Cell Death Dis.
Interaction of Sirt3 with OGG1 contributes to repair of mitochondrial DNA and protects from apoptotic cell death under oxidative stress
Cell Death Dis.
The growing landscape of lysine acetylation links metabolism and cell signalling
Nat. Rev. Mol. Cell Biol.
Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria
Biochemistry
Cited by (88)
Pyrazolone derivatives as potent and selective small-molecule SIRT5 inhibitors
2023, European Journal of Medicinal ChemistryCitation Excerpt :SIRT5, which is predominantly found in the mitochondrial matrix, can effectively catalyze the removal of malonyl, succinyl, and glutaryl groups from its substrate protein in vitro and in vivo. In contrast, SIRT5 has weak deacetylase activity [6–8]. Recent studies suggest that SIRT5 plays a pivotal role in regulating ammonia detoxification, fatty acid oxidation, cellular respiration, ketone body formation, tricarboxylic acid cycle, glycolysis, and reactive oxygen species metabolism [9–13].
Identification of 2-hydroxybenzoic acid derivatives as selective SIRT5 inhibitors
2022, European Journal of Medicinal ChemistryDevelopment of hetero-triaryls as a new chemotype for subtype-selective and potent Sirt5 inhibition
2022, European Journal of Medicinal ChemistryPlant-derived compounds, vitagens, vitagenes and mitochondrial function
2022, PharmaNutrition