Sirt4: A Multifaceted Enzyme at the Crossroads of Mitochondrial Metabolism and Cancer.

Daniela Tomaselli,Clemens Steegborn,Dante Rotili,Antonello Mai

doi:10.3389/fonc.2020.00474

Daniela Tomaselli, Clemens Steegborn + Show 2 more

Open Access

https://doi.org/10.3389/fonc.2020.00474

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Abstract

Sirtuins are NAD+-dependent deacylases that play crucial roles in the regulation of cellular metabolism, and as a result, are implicated in several diseases. The mitochondrial sirtuin Sirt4, for a long time considered as mainly a mono-ADP-ribosyltransferase, recently has shown a robust deacylase activity in addition to the already accepted substrate-dependent lipoamidase and deacetylase properties. Through these and likely other enzymatic and non-enzymatic activities, Sirt4 closely controls various metabolic events, and its dysregulation is linked to various aging-related disorders, including type 2 diabetes, cardiac hypertrophy, non-alcoholic fatty liver disease, obesity, and cancer. For its capability to inhibit glutamine catabolism and for the modulation of genome stability in cancer cells in response to different DNA-damaging conditions, Sirt4 is proposed as either a mitochondrial tumor suppressor or a tumor-promoting protein in a context-dependent manner. In addition to what is already known about the roles of Sirt4 in different biological settings, further studies are certainly still needed in order to validate this enzyme as a new potential target for various aging diseases.

Highlights

Sirt4 is one of the three mitochondrial sirtuins and, despite that it was firstly described as a mono-ADP-ribosyltransferase, nowadays it has demonstrated a robust deacylase activity toward 3-hydroxy-3-methyl-glutarylated (HMG) lysine residues [1] as well as substrate-specific lipoamidase and deacetylase properties [2, 3]
Beyond this capability to regulate energy and glutamine metabolism, an important Sirt4 activity is its lipoamidase-mediated inhibition of pyruvate dehydrogenase (PDH), the crucial multi-component enzymatic complex that modulates the entrance of acetylCoA deriving from glycolysis into the tricarboxylic acids (TCA) cycle, identifying Sirt4 as a “guardian of cellular metabolism” [9]
While Sirt4 associates with different biotin-dependent carboxylases, including MCCC, and is able to hydrolyze various lysine-biotinylated peptides in vitro, the capability to remove biotinyl groups from substrate proteins in vivo has not been investigated yet [3]

Summary

Introduction

Sirt4 is one of the three mitochondrial sirtuins and, despite that it was firstly described as a mono-ADP-ribosyltransferase, nowadays it has demonstrated a robust deacylase activity toward 3-hydroxy-3-methyl-glutarylated (HMG) lysine residues [1] as well as substrate-specific lipoamidase and deacetylase properties [2, 3]. Sirt4 was shown to deacetylate and inhibit the activity of malonyl-CoA decarboxylase (MCD) in white adipose tissue and skeletal muscle, thereby regulating fatty acid oxidation (FAO) and biosynthesis processes [11] (Figure 1). The mitochondrial trifunctional protein α-subunit (MTPα) has been identified as a substrate of Sirt4 deacetylation in hepatocytes, highlighting the capability of this enzyme to inhibit FAO in the liver [12] (Figure 1).

Results

Conclusion