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

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.

Keywords: cancer; metabolism; mitochondria; protein deacylation; sirtuins.

Figure 1

Sirt4 and its substrates in the mitochondrial metabolic pathways. Sirt4 modulates directly or indirectly the activity of several targets (depicted in yellow) that play key roles in various metabolic processes. Green arrows and red lines indicate the promotion/activation and suppression/inhibition of a specific activity, respectively. (A) Sirt4 modulation of lipid metabolism. (B) Sirt4 inhibition of PDH through lipoamidase activity. (C) Sirt4 modulation of insulin secretion and sensitivity. (D) Sirt4 effects on mitochondrial oxidative stress. (E) Sirt4 and cancer. ACC, acetyl-CoA carboxylase; Ac-CoA, acetyl coenzyme A; AMPK, AMP-activated protein kinase; ANT2, adenine nucleotide translocator 2; ATP, adenosine triphosphate; CPT1, carnitine palmitoyl-transferase 1; CtBP, C-terminal binding protein; DLAT, dihydrolipoyllysine acetyltransferase; FA, fatty acids; FAO, fatty acids oxidation; GDH, glutamate dehydrogenase; GLS, glutaminase; IDE, insulin degrading enzyme; MCCC, 3-methylcrotonyl-CoA carboxylase; MC-CoA, 3-methylcrotonyl-CoA; MGc-CoA, 3-methylglutaconyl-CoA; MCD, malonyl-CoA decarboxylase; MnSOD, manganese-dependent superoxide dismutase; mTORC1, mammalian target of rapamycin complex 1; MTPα, mitochondrial trifunctional protein α; PGC-1α, peroxisome proliferator-activated receptor gamma co-activator 1α; PDH, pyruvate dehydrogenase; PPARα, peroxisome proliferator-activated receptors α; ROS, reactive oxygen species; TCA, tri-carboxylic acid; TF, transcription factor.