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Review
. 2018 Mar 10;28(8):643-661.
doi: 10.1089/ars.2017.7290. Epub 2017 Oct 20.

The Role of Sirtuins in Antioxidant and Redox Signaling

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Free PMC article
Review

The Role of Sirtuins in Antioxidant and Redox Signaling

Chandra K Singh et al. Antioxid Redox Signal. .
Free PMC article

Abstract

Significance: Antioxidant and redox signaling (ARS) events are regulated by critical molecules that modulate antioxidants, reactive oxygen species (ROS) or reactive nitrogen species (RNS), and/or oxidative stress within the cell. Imbalances in these molecules can disturb cellular functions to become pathogenic. Sirtuins serve as important regulators of ARS in cells. Recent Advances: Sirtuins (SIRTs 1-7) are a family of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases with the ability to deacetylate histone and nonhistone targets. Recent studies show that sirtuins modulate the regulation of a variety of cellular processes associated with ARS. SIRT1, SIRT3, and SIRT5 protect the cell from ROS, and SIRT2, SIRT6, and SIRT7 modulate key oxidative stress genes and mechanisms. Interestingly, SIRT4 has been shown to induce ROS production and has antioxidative roles as well.

Critical issues: A complete understanding of the roles of sirtuins in redox homeostasis of the cell is very important to understand the normal functioning as well as pathological manifestations. In this review, we have provided a critical discussion on the role of sirtuins in the regulation of ARS. We have also discussed mechanistic interactions among different sirtuins. Indeed, a complete understanding of sirtuin biology could be critical at multiple fronts.

Future directions: Sirtuins are emerging to be important in normal mammalian physiology and in a variety of oxidative stress-mediated pathological situations. Studies are needed to dissect the mechanisms of sirtuins in maintaining redox homeostasis. Efforts are also required to assess the targetability of sirtuins in the management of redox-regulated diseases. Antioxid. Redox Signal. 28, 643-661.

Keywords: antioxidants; oxidative stress; redox signaling; sirtuins.

Figures

<b>FIG. 1.</b>
FIG. 1.
Schematic representation showing interaction of sirtuins with NRF2 that regulates the expression of several antioxidant and detoxification genes. Under oxidative stress, the KEAP1-CUL3 ubiquitination system is disrupted, which allows NRF2 to translocate into the nucleus where it forms a heterodimer with one of the Maf proteins and binds to the ARE or ERE in the promoter region of antioxidative stress response genes resulting in mitochondrial biogenesis and antioxidant redox signaling. ARE, antioxidant response element; CUL3, cullin 3; ERE, electrophilic response element; GSH, glutathione; HO-1, heme oxygenase 1; KEAP1, kelch-like ECH-associated protein 1; NRF2, nuclear factor E2-related factor 2; ROS, reactive oxygen species; SOD, superoxide dismutase.
<b>FIG. 2.</b>
FIG. 2.
Mechanistic illustration of the sirtuins in ARS pathways. Sirtuins are involved in regulating ARS in numerous ways. SIRTs 1–7 have been found to be involved in modulating levels of ROS, antioxidant enzymes, DNA repair, mitochondrial dysfunction, and oxidative stress in the cell through key transcription factors such as NRF2, p53, NF-κB, FOXO, and PGC-1α. Question marks (?) indicate that exact mechanism is unknown. When cells become stressed, ROS production is increased, and coenzyme NAD+ (green diamond) activates various sirtuins (yellow ovals). In addition, sirtuins regulate the activity of the ARE (orange ovals), which in turn modulates the transcription of pro- and antioxidant genes to maintain redox signaling cascades. ADP, adenosine diphosphate; ARS, antioxidant and redox signaling; CAT, catalase; FOXO, class O of forkhead box transcription factors; G6PD, glucose 6-phosphate dehydrogenase; NAD, nicotinamide adenine dinucleotide; NF-κB, nuclear factor kappa B subunit; PARP1, poly (ADP-ribose) polymerase 1; PGAM2, phosphoglycerate mutase; SIRT, sirtuin.
<b>FIG. 3.</b>
FIG. 3.
Dynamic interaction network of sirtuins. A sirtuin interaction network was generated via Ingenuity Pathway Analysis (QIAGEN) to highlight how sirtuins interact among themselves. Molecular interactions are denoted by arrows with solid lines showing robust correlation and dashed lines showing less frequent correlations. In addition to SIRTs 1–7, several other proteins have also appeared as mediators in the sirtuin network (indicated with uncolored background). Blunt-ended lines indicate protein/protein interactions and arrowed lines indicate that one is affecting the expression of other. The interactions among sirtuins are denoted with blue lines. The illustration shows that sirtuins closely interact with each other, either directly or through very few intermediaries. This network suggests that the network of ARS molecules may be impacted by more than one sirtuin, and that understanding the interplay between sirtuins is crucial to understand sirtuin-mediated redox homeostasis. AACS, acetyl-CoA synthetase.
<b>FIG. 4.</b>
FIG. 4.
Molecular associations of sirtuins with ARS-related targets. The figure illustrates the wide variety of ARS-related targets that have been shown to be regulated with sirtuins. Interestingly, several of the proteins appear to have common targets for SIRTs 1–7. For example, NRF2 appears to be a common target for SIRTs 1–3, 5, and 6, to mediate antioxidative genes. The large number of targets identified for SIRT1 suggests it may be more involved in ARS regulation than other sirtuins, although it may be a by-product of its popularity in research and early identification instead.
<b>FIG. 5.</b>
FIG. 5.
A schematic representation of sirtuin-mediated redox homeostasis. Sirtuins contribute to redox homeostasis maintenance by balancing antioxidant enzymes and pro-oxidant radicals. As illustrated, sirtuins regulate the expression and activity of antioxidative enzymes and the production of pro-oxidants as well. Pro-oxidants also affect the activity of sirtuins through alteration of the NAD+/NADH ratio, allowing for a feedback loop that helps prevent the cell from entering or maintaining a state of oxidative stress. NAD, nicotinamide adenine dinucleotide.

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