Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Apr 20;22(12):1060-77.
doi: 10.1089/ars.2014.6213. Epub 2015 Feb 10.

Mitochondrial sirtuins and their relationships with metabolic disease and cancer

Surinder Kumar  1 , David B Lombard
Affiliations
Review

Mitochondrial sirtuins and their relationships with metabolic disease and cancer

Surinder Kumar et al. Antioxid Redox Signal. .

Abstract

Significance: Maintenance of metabolic homeostasis is critical for cellular and organismal health. Proper regulation of mitochondrial functions represents a crucial element of overall metabolic homeostasis. Mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) play pivotal roles in promoting this homeostasis by regulating numerous aspects of mitochondrial metabolism in response to environmental stressors.

Recent advances: New work has illuminated multiple links between mitochondrial sirtuins and cancer. SIRT5 has been shown to regulate the recently described post-translational modifications succinyl-lysine, malonyl-lysine, and glutaryl-lysine. An understanding of these modifications is still in its infancy. Enumeration of SIRT3 and SIRT5 targets via advanced proteomic techniques promises to dramatically enhance insight into functions of these proteins.

Critical issues: In this review, we highlight the roles of mitochondrial sirtuins and their targets in cellular and organismal metabolic homeostasis. Furthermore, we discuss emerging roles for mitochondrial sirtuins in suppressing and/or promoting tumorigenesis, depending on the cellular and molecular context.

Future directions: Currently, hundreds of potential SIRT3 and SIRT5 molecular targets have been identified in proteomic experiments. Future studies will need to validate the major targets of these enzymes, and elucidate how acetylation and/or acylation modulate their functionality. A great deal of interest exists in targeting sirtuins pharmacologically; this endeavor will require development of sirtuin-specific modulators (activators and inhibitors) as potential treatments for cancer and metabolic disease.

PubMed Disclaimer

Figures

<b>FIG. 1.</b>
FIG. 1.
Catalytic activities of mammalian sirtuins. SIRT1, SIRT2, and SIRT7 function primarily as deacetylases, whereas other mammalian sirtuins catalyze alternative reactions, in addition to or instead of deacetylation. SIRT4 acts as both a deacetylase and an ADP-ribosyltransferase. SIRT5 catalyzes desuccinylation, demalonylation, and deglutarylation. SIRT6 catalyzes ADP-ribosylation and deacylation, in addition to deacetylation. Only activities shown to be biologically significant are depicted.
<b>FIG. 2.</b>
FIG. 2.
Subcellular localization of mammalian sirtuins. SIRT7 is present in the nucleus, whereas SIRT1, SIRT2, and SIRT6 are both nuclear and cytosolic. SIRT3, SIRT4, and SIRT5 primarily reside in the mitochondrial matrix; SIRT5 is also found in the cytosol and the nucleus.
<b>FIG. 3.</b>
FIG. 3.
Schematic representation of SIRT3 targets and downstream functions. SIRT3 deacetylates and activates multiple targets (green rounded rectangles), which can either directly regulate key cellular and physiological processes (yellow) or alter the activity (blue ellipse) or expression levels (blue rectangle) of downstream factors. Upward and downward red arrows designate promotion or suppression of particular activity or expression. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 4.</b>
FIG. 4.
Overview of SIRT4 target substrates and cellular functions. SIRT4 directly (red rounded rectangles) or indirectly (green ellipses) modulates the activity of various target substrates, which either regulate aspects of fatty acid metabolism (yellow rectangles) or play crucial roles in other cellular processes (blue rounded rectangles). Upward and downward red arrows indicate the promotion or suppression of a particular activity, gene expression, or physiological activity. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 5.</b>
FIG. 5.
Major targets regulated by SIRT5. SIRT5 deacetylates, desuccinylates, demalonylates, and/or deglutarylates multiple metabolic enzymes to activate (blue ellipses) or inhibit (green ellipses), either increasing (yellow rounded rectangle with upward red arrow) or decreasing (yellow rounded rectangles with downward red arrow) the levels/activity of particular compound/cellular activity. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 6.</b>
FIG. 6.
Overview of interplay between mitochondrial sirtuins. Enzymes involved in ketogenesis (blue boxes) and urea cycle (gray boxes) are activated by both SIRT3 and SIRT5. While SIRT5 inhibits the enzymatic activities of glucose metabolism (magenta box), SIRT3 activates them to suppress metabolic reprogramming and tumorigenesis. SIRT3 also suppresses tumorigenesis by decreasing ROS levels through activation of antioxidant machinery (green box). SIRT5 activates SOD1 (orange box) to maintain ROS below toxic levels to support tumor cell survival. SIRT3 also shares common target/pathways with SIRT4. SIRT3 promotes FAO by activating LCAD and AMPK (red box), whereas SIRT4 represses FAO through inhibition of MCD, PPARα, and AMPK (pink box). Similarly, SIRT3 activates GDH (violet box), which is inhibited by SIRT4. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A, Deng CX, and Finkel T. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci U S A 105: 14447–14452, 2008 - PMC - PubMed
    1. Ahuja N, Schwer B, Carobbio S, Waltregny D, North BJ, Castronovo V, Maechler P, and Verdin E. Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. J Biol Chem 282: 33583–33592, 2007 - PubMed
    1. Alam N. and Saggerson ED. Malonyl-CoA and the regulation of fatty acid oxidation in soleus muscle. Biochem J 334 (Pt 1): 233–241, 1998 - PMC - PubMed
    1. Albani D, Ateri E, Mazzuco S, Ghilardi A, Rodilossi S, Biella G, Ongaro F, Antuono P, Boldrini P, Di Giorgi E, Frigato A, Durante E, Caberlotto L, Zanardo A, Siculi M, Gallucci M, and Forloni G. Modulation of human longevity by SIRT3 single nucleotide polymorphisms in the prospective study “Treviso Longeva (TRELONG)”. Age (Dordr) 36: 469–478, 2014 - PMC - PubMed
    1. Alhazzazi TY, Kamarajan P, Joo N, Huang JY, Verdin E, D'Silva NJ, and Kapila YL. Sirtuin-3 (SIRT3), a novel potential therapeutic target for oral cancer. Cancer 117: 1670–1678, 2011 - PMC - PubMed

Publication types

LinkOut - more resources