Voznesenskaya T. Y., Stupchuk M. S., Kaleinikova O. N., Blashkiv T. V.

SIRT1 AS A KEY CELL REGULATOR OF METABOLISM AND OXIDATIVE STRESS


About the author:

Voznesenskaya T. Y., Stupchuk M. S., Kaleinikova O. N., Blashkiv T. V.

Heading:

LITERATURE REVIEWS

Type of article:

Scentific article

Annotation:

Sirtuins (silent information regulator (SIRTs) proteins), NAD + dependent enzymes with deacetylase and/or mono-ADP-ribosyltransferase activity, are emerging as key antiaging molecules. The aim of the present review is to summarize current knowledge on the role of SIRT1 as a key cell regulator of metabolism and oxidative stress. In the last 15 years, the complex process of cellular aging has been tightly linked to the action of sirtuins. Sirtuins are formerly known as class III nicotinamide adenine dinu-cleotide (NAD + ) dependent histone deacetylases (HDACs), although they may use a variety of substrates that include structural proteins, metabolic enzymes, and histones. All sirtuins remove predominantly acetyl groups from cellular proteins, and this posttranslational chemical modification affects significantly protein localization and function. In this process, the acetyl group from the acetylated substrate is transferred to the ADP-ribose portion of NAD, releasing 2 -O-acetyl-ADP-ribose, nicotinamide, and the deacetylated substrate as products. After the first discovery of the yeast ortholog SIRT2, sirtuins have been identified in prokaryotes and in metazoan. To date, seven members of the sirtuin family have been identified in mammals (SIRT1-7) and each member has peculiar subcellular localization, function, and substrate specificity. SIRT1 and SIRT2 have been found in both the nucleus and cytosol; on the other hand, SIRT3, SIRT4, and SIRT5 have been found exclusively in mitochondria, while SIRT6 and SIRT7 have been localized only in the nuclear compartment. Strong experimental evidence supports the notion that SIRT1 plays a crucial role in sensing and modulating the cellular redox status thus providing protective effects in cells and tissues exposed to oxidative stressors in vitroand in vivo. SIRT1 is able to directly deacetylate key proteins involved in the cellular stress response, such as forkhead box O (FoxO) transcription factors. In in vitrostudy, some authors established the fact that SIRT1 activates proliferator-activated receptor coactivator-1 (PGC-1), maintaining its deacetylated active form into the nucleus, where it activates genes involved in a variety of biological processes and responses, including antiox-idative protection, mitochondrial biogenesis, glucose/fatty acid metabolism, and oxidative phosphorylation (OXPHOS). The nuclear factor B (NF-B), which is a major inducer of inflammatory responses, was the first eukaryotic transcription factor described to respond directly to H 2O2 -induced oxidative stress. NF-B deacetylated and inactivated by SIRT1 exhibits impaired downstream signalling and lowers the cellular ROS load by promoting the resolution of inflammation. The majority of the work carried out so far on the role of sirtuins in reproductive functions has focused on SIRT1 and SIRT3, as the main redox regulators. As reported above, SIRT1 as the major nuclear deacetylase plays a pivotal role in the transcriptional response to changes in redox conditions and SIRT3, as the major mitochondrial deacetylase, acts as the in situregulator of proteins which ameliorate damage in mitochondria, the major source of ROS in the cell. Resveratrol (3,5,4-trihydroxystilbene) is the most potent in vitro natural SIRT1 activator. The search for a synthetic SIRT1 activator with greater efficiency, solubility and bioavailability becomes even more relevant in recent years. Our knowledge of sirtuins has grown exponentially over the last few years. As reported above, SIRT1 as the major nuclear deacetylase plays a pivotal role in the transcriptional response to changes in redox conditions. In search for strategies aimed at preventing oxidative threat to female fertility, an animal using the influence of SIRT1 activators/blockers, a key cellular metabolism regulator and oxidative stress, is assessed on the functional state of the ovary under conditions of experimental systemic damage.

Tags:

sirtuins, SIRT1, oxidative stress

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Publication of the article:

«Bulletin of problems biology and medicine» Issue 1 Part 1 (142), 2018 year, 20-25 pages, index UDK 616.092.4

DOI: