University of Oulu

Elkhwanky, M.-S., & Hakkola, J. (2018). Extranuclear Sirtuins and Metabolic Stress. Antioxidants & Redox Signaling, 28(8), 662–676.

Extranuclear sirtuins and metabolic stress

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Author: Elkhwanky, Mahmoud S.1,2; Hakkola, Jukka1,2
Organizations: 1Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, Oulu, Finland
2Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 3.7 MB)
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Language: English
Published: Mary Ann Liebert, 2018
Publish Date: 2019-07-02


Significance: Extranuclear sirtuins in cytosol (SIRT2) and mitochondria (SIRT3, SIRT4, and SIRT5) are key regulators of metabolic enzymes and the antioxidative defense mechanisms. They play an important role in the adjustment of metabolic pathways in alterations of the nutritional status.

Recent Advances: Recent studies have shown that in addition to lysine deacetylation, sirtuins catalyze several different lysine deacylation reactions, removal of lipid modifications, and adenosine diphosphate-ribosylation. Large-scale studies have revealed hundreds of target proteins regulated by different sirtuin modifications.

Critical Issues: Sensing of the metabolic state and regulation of the sirtuin function and expression are critical components of the machinery, optimizing cellular functions in the switch from fed to fasting condition. Overfeeding, obesity, and metabolic diseases cause metabolic stress that dysregulates the sirtuins, which may play a role in the pathogenesis and complications of metabolic diseases such as type 2 diabetes, fatty liver disease, and cardiac diseases. In the current review, we will discuss the significance of the extranuclear sirtuins as metabolic regulators and in protection against the reactive oxygen species, and also how these sirtuins are regulated by metabolic status and their putative role in metabolic diseases.

Future Directions: To efficiently utilize sirtuins as drug targets for treatment of the metabolic diseases, better understanding of the sirtuin functions, targets, regulation, and cross talk is needed. Furthermore, more studies in humans are needed to confirm the many observations mainly made in animal and cell models so far. Antioxid. Redox Signal. 28, 662–676.

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Series: Antioxidants & redox signaling
ISSN: 1523-0864
ISSN-E: 1557-7716
ISSN-L: 1523-0864
Volume: 28
Issue: 8
Pages: 662 - 676
DOI: 10.1089/ars.2017.7270
Type of Publication: A2 Review article in a scientific journal
Field of Science: 3111 Biomedicine
Funding: The original research of the authors has been financially supported by the grants from the Academy of Finland (grant 286743),) and the Novo Nordisk Foundation (grant NNF15OC0015846) and the Diabetes research Foundation.
Academy of Finland Grant Number: 286743
Detailed Information: 286743 (Academy of Finland Funding decision)
Copyright information: © 2018, Mary Ann Liebert, Inc. Final publication is available from Mary Ann Liebert, Inc., publishers