Elsevier

Experimental Gerontology

Volume 61, January 2015, Pages 130-141
Experimental Gerontology

Review
Mitochondrial sirtuins: Emerging roles in metabolic regulations, energy homeostasis and diseases

https://doi.org/10.1016/j.exger.2014.12.004Get rights and content

Highlights

  • Paper explores the localization, enzymatic activities and regulation of mitochondrial sirtuins.

  • Paper updates recent knowledge on the role of mitochondrial sirtuins in regulation of metabolism and energy homeostasis.

  • Paper explains the role of mitochondrial sirtuins in oxidative stress, apoptosis, and mitochondrial biogenesis.

  • Paper describes the role of sirtuins in the regulation of metabolic diseases resulting from mitochondrial impairments.

  • Paper explores therapeutic applications of targeting mitochondrial sirtuins by bioactive compounds in human diseases.

Abstract

The energy production and metabolic homeostasis are well-orchestrated networks of carbohydrate, lipid and protein metabolism. These metabolic pathways are integrated by a key cytoplasmic organelle, the mitochondria, leading to production of many metabolic intermediates and harvest cellular energy in the form of ATP. Sirtuins are a highly conserved family of proteins that mediate cellular physiology and energy demands in response to metabolic inputs. Mitochondria inhabit three main types of sirtuins classified as Sirt3, Sirt4 and Sirt5. These sirtuins regulate mitochondrial metabolic functions mainly through controlling post-translational modifications of mitochondrial protein. However, the biological mechanism involved in controlling mitochondrial metabolic functions is not well understood at this stage. In this review the current knowledge on how mitochondrial sirtuins govern mitochondrial functions including energy production, metabolism, biogenesis and their involvement in different metabolic pathways are discussed. The identifications of potential pharmacological targets of sirtuins in the mitochondria and the bioactive compounds that target mitochondrial sirtuins will increase our understanding on regulation of mitochondrial metabolism in normal and disease state.

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).

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